PCX _
INTERNATIONAL APPLICATION PUBLISH ED 1^7r";;e PATENT COOPERATION TREATY (PCT)
WORLD INTm-LECTUAL PROPERTY ORGANIZATION
international Bureau
(51) International Patent Classiflcation 6 :
C07C 275/28, C07D 213/75, 257/04,
23m2, 401/12, A61K 31/17, 31/44,
^Kli'.^®^"^ 307/38, 277/28,
233/54, C07C 311/21. C07D 333/20
Al
(11) International Publication Number:
(43) International Publication Date:
WO 96/10559
11 April 1996 (11.04.96)
(21) International Application Number: PCT/JP95/01982
(22) International Filing Date: 29 September 1995 (29.09.95)
(30) Priority Data:
9419970.0
9506720.3
9514021.6
4 October 1994 (04.10.94) GB
31 March 1995 (31.03.95) GB
10 July 1995 (10.07.95) QB
(71) Applicant (for all designated States except US): FUJISAWA
PHARMACEUTICAL CO.. LTD. [JP/^]; 4-7. Do/homacW
3-chome, Chuo-ku. Osaka-shi. Osaka 541 (JP).
(72) Inventors; and
(75) I»''^nto«/Applicante (for US only): TERASAWA. Takeshi
UP/JP]; 1625-302, Matsugaokanakamachi. Kawachinagano-
shi Osaka 586 (JP). TANAKA. Akira [JP/JP]; 9-1(^302
Nakano-cho, Takarazuka-shi. Hyogo 665 (JP) CHIBa'
J^n'7™!'4'r^J' Naka^sfji-cho. Nar^-sS^ai'
630 (JP). TAICASUGI. Hisashi [JP/JP]; 3-116-10, Mozu
Umckita. Sakaj-shi, Osaka 591 (JP).
(74) Agent: SEKI, Hideo; Fujisawa Phannaceutical Co.. Ltd Osaka
r^'^^'^i.i'^- ^^hima 2-chomc, Yodogawa-ku, Osaki-shi
Osaka 532 (JP).
(81) Designated States: AU, CA, CN, HU, JP, KR, MX RU US
Eur^ean patent (AT, BE, CH, DE, DK. ES, Fr' Gb' Gr'
IE, IT, LU, MC. NL, PT. SE).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments. ^ ^
(54) Title: UREA DERIVATIVES AND THEIR USE AS ACAT-INHIBITORS
(57) Abstract
,1-
{CH2)
,-N-c!-NH-R-
(I)
(1)
Urea derivatives of formula
(I), wherein R' is a group of
formula (I) (in which R4 is
aryl which may have suitable
substituent(s), or heterocyclic
group which may have suitable
substituent(s), and Y is bond,
lower alkylene, -S-, -O- (a)
-CH-, -CONH-. (b), (in which
is lower alkyl). -NHSO2-
-SO2NH-. -SO2NHCO- or
-CONHSO2-): or thiazolyl,
imidazolyl, pyrazolyl, pyridyl '
SSiy^iliw^^^^^^^^^ is lower alkyl. lower alkoxy(lower)alky..
have suitable substituent(s) or heterocyclic group ih r^rhavei ^hich may
salt thereof which ar. usef.1 as a m Jicame^nt i^ the ta^en't^:^ '^S^.^^S^^^^^ '^l^^^"^
II (a)
-C-
-N-CO-
L
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States
applications under the PCT.
AT
Austria
AH
Auscralia
BB
Barbados
BE
Belgium
BF
Buikina Paso
BG
Bulgaria
BJ
Benin
BR
Brazil
BY
Belarus
CA
Canada
CF
CenrnJ African Republic
CG
Congo
CH
Switzerland
CI
C8<e d'lvoire
CM
Cameroon
CN
China
OS
Czechoslovakia
CZ
Czech Republic
DE
Germany
DK
Denmark
E5
Spain
FI
Finland
FR
France
GA
Gabon
party to the PCT on the front pages
GB
United Kingdom
GE
Georgia
GN
Guinea
GR
Greece
HU
Hungary
IE
Ireland
IT
Italy
JP
Japan
KE
Kenya
KG
Kyigystan
KP
Democratic People's Republic
of Korea
KR
Republic of Korea
KZ
Kazakhstan
LI
Liechtenstein
LK
Sri Lanka
LU
Luxembourg
LV
Latvia
MC
Monaco
MD
Republic of Moldova
MG
Madagascar
ML
Mali
MN
Mongolia
pamphlets publishing international
MR
Mauritania
MW
Malawi
NE
Niger
NL
Netherlands
NO
Norway
NZ
New Zealand
PL
Poland
PT
Portugal
RO
Romania
RU
Russian Federation
SD
Sudan
SE
Sweden
SI
Slovenia
SK
Slovakia
SN
Senegal
TD
Chad
TG
Togo
TJ
Tajikistan
TT
Trinidad and Tobago
UA
Ukrame
US
United States of America
UZ
Uzbekistan
VN
Viet Nam
wo 96/10559
PCT/JP95/01982
- 1 -
DESCRIPTION
UREA DERIVATIVES AND THEIR USEAS ACAT-INHIBITORS
TECHNICAL FIELD
This invention relates to new urea derivatives and
pharmaceutically acceptable salts thereof which are useful
as a medicament.
BACKGROUND ART
Some urea derivatives have been known as acyl-CoA :
cholesterol acyl transferase enzyme (hereinafter, ACAT)
inhibitors, for example, in U.S. Patent Nos. 4,473,579 and
4,623,662, EP Patent Application Publication Nos. 0354994
0399422 and 0512570 and PCT International Publication Nos!
WO 91/13871, WO 93/24458 and WO 94/26738.
DISCLOSURE OF INVENTION
This invention relates to new urea derivatives and
pharmaceutically acceptable sales thereof which have an
inhibitory activity against ACAT and an advantage of good
absorption into blood on oral administration, to processes
for the preparation thereof, to a pharmaceutical
composition comprising the sa.me and to a method for the
prevention and/or treatment of hypercholesterolemia,
hyperlipidemia, atherosclerosis or diseases caused thereby.
One object of this invention is to provide new and
useful urea derivatives and pharmaceutically acceptable
salts which possess an inhibitory activity against ACAT.
Another object of this invention is to provide
processes for preparation of said urea derivatives and
salts thereof.
A further object of this invention is to provide a
pharmaceutical composition comprising, as an active
ingredient, said urea derivatives and pharmaceutically
wo 96/10559
PCT/JP95/01982
- 2 -
acceptable salt thereof.
Still further object of this invention is to provide a
therapeutic method for the prevention and/or treatment of
hypercholesterolemia, hyperlipidemia, atherosclerosis or
5 diseases caused thereby in human beings or animals, using
said urea derivatives and pharmaceut ically acceptable salts
thereof .
High levels of blood cholesterol and blood lipids are
conditions which are involved in the onset of
10 atherosclerosis.
It is well known that inhibition of ACAT-catalyzed
cholesterol esterif ication could lead to diminish
intestinal absorption of cholesterol as well as a decrease
in the intracellular accumulation of cholesterol esters in
15 the intima of the arterial wall. Therefore, ACAT
inhibitors are useful for the prevention and/or treatment
of hypercholesterolemia, hyperlipidemia, atherosclerosis of
diseases caused thereby such as cardiac insufficiency (e.g.
angina pectoris, myocardial infarction, etc.),
20 cerebrovascular disturbance (e.g. cerebral infarction,
cerebral apoplexy, etc. ) , arterial aneurism, peripheral
vascular disease, xanthomas, restenosis after percutaneous
transluminal coronary angioplasty, or the like.
25 The object urea derivatives of this invention are new
and can be represented by the following general formula
(I) :
30
O
R^- (CH2 ) j^-N-C-NH-R-
R^
(i:
35
wo 96/10559
PCT/JP95/01982
- 3
wherein
is a group of the formula :
r4
(in which
r4
is aryl which may have suitable substituent (s) ,
or heterocyclic group which may have
suitable substituent (s ) , and
C
Y is bond, lower alkylene, -s-, -c-, -L, =c^-
-CONH-, -N-CO-, (in which r7 is lower
^'^ alkyl),
-NHSO2-, -SO2NH-, -SO2NKCO- or -CONHSO0-);
or
thiazolyl, imidazolyl, pyrazolyl, pvridvl, thie^v^
furyl, xsoxazolyl or chromanyl, each of which may have
suitable substituent (s) ;
r2 is lower alkyl, lower alkoxy ( lower ) alkyl , cycloalky^
ar (lower) alkyl which may have suitable substituent '(s)
^ heterocyclic group or heterocyclic (lower) alkyl,
R is aryl which may have suitable substituent (s ) or
heterocyclic group which may have suitable
substituent (s) , and
n is 0 or 1 .
The object compound (I) of the present invention c=>n
be prepared by the following processes.
wo 96/10559
PCT/JP95/01982
- 4 -
Process (JJ.
r1- (CH2)n-NH
K
(II)
or a salt thereo;
10
15
0=C=N-R-^
(III)
or a sal"c chereof
20
O
1 II
R-^- (CH2 ) ^-N-C-NH-R--
I o
R"-
25
(I)
or a salt thereof
Process (2'
30
R^ - (CH2)p_-NH
I o
R-
(II)
or a salt thereof
+
( IV)
or a salt thereo:
35
wo 96/10559
PCT/JP95/01982
5 -
formation of
ureido group
10
R^-(CH2)^-N-C-NH-r3
' 9
R-
15
20
(I)
or a salt thereof
O
H-'-- (Cn2 ) _^-N-C-NK-r3
R'
(la)
or a salt thereof
25
30
oxidation
35
wo 96/10559
PCT/JP95/01982
D
R^- CCH2)p_-N-C-NK-Rg
R-
5
(lb)
or a salt thereof
10
wherein
r2, r3 and n are each as defined above,
3
pyridyl having two lower alkylthio and lower alkyl,
and
pyridyl having two lower alkylsulfonyl and lower
alkyl; pyridyl having two lower alkylsulf inyl and
lower alkyl; or pyridyl having lower alkylsulfonyl,
lower alkylsulf inyl and lower alkyl.
The starting compound can be prepared by the followi
processes .
Process (A)
25
O
30
(V)
35
wo 96/10559
PCT/JP95/01982
- 7 -
0
(VI)
(VII)
or a sale thereof
, H2M-NH2
0
(VIII)
or a salt thereof
(IXa)
or a salt thereof
wo 96/10559
PCT/JP95/01982
Process L£l
- 8
r1 - CN
(IX)
or a salt thereo:
10
reduction
15
r1 - CHO
20
-ocess [
(X)
or a salt thereof
25
(XI)
or a salr thereof
30
(XII)
or a salz thereof
35
wo 96/10559
PCT/JP95/01982
- 9 -
(Xa)
or a salt thereof
Prorq-.c;c; (n<
- B(OH)2
(XIII)
or a salt thereof
(XII )
or a salt thereof
V
(Xb)
or a salt thereof
wo 96/10559
PCT/JP95/01982
Process LEJ
- 10 -
,1 _
CHO
10
15
(X)
or a salt thereof
i) R'^-NH
(XIV)
or a salt thereof
ii) reduction
20
R^-CH2-NH
(Ila)
or a salt thereof
25
wherein R , R , and R are each as defined above,
is lower alkoxy,
R^ is lower alkyl,
Rg is aryl which may have suitable
substituent ( 5 ) , and
X is a leaving group.
35
Suitable pharmaceutical ly acceptable salts of the
wo 96/10559
PCT/JP95/01982
- 11 -
object coniDound (i) =r-^
Ui are conventional non-toxic ^^ir^
a sa.c with an inorganic base, for examm »
alkali metal <=r^n- , example, an
/ ' -^i^^' potassium sa^^
etc.), an alkaline earth metal salt , r.
-gnesium salt, etc.), an an^onium sal': 'I Z^^!:^'''
organic .ase, .or example, an organic amine .t V^
tr.eth.lamine salt, p,ri.ine salt, pieoline salt,
ethanolamme salt, triPth^r.^i
triethanoiamme salr, di-w-T^K
-It, N,N-d.ben.yXethyIenedia...ne .aX., ^^^^^'^^'^^'^^^-^
an inorganic acid addition ^ r / '
hydrobron,ide sulfate T °! 'hydrochloride,
'^""^te, phosphate, etc.); an organic
carboxyl.c or sulfonic acid addition salt ,e o
acetate, trifluoroacetate, .aieate, tartrate '
-tra.., .ethanesuifonate, ben.enesul'f onate '
toluenesulfonate e-tr- ■. • = ^ .
i^Le, etc.;; a salt with a bas^c ^r-.-w
amino acid (e^ n = • ■ "as_c or acidic
acia (e.g., argmine, asDartic acid m..^ ■
dcia, glutamic acid.
etc. )
^"^^ subsequent descriptions o^ th.
P esent specification, suitable examples and iJu t;at.o^
nt -^-^ P^esent mve^ :r
intend, to include within the scooe t^ev-eof .r. . ■
detail as follows. ' explained
The term "lower" is used to intend a grouo havina i ^
6. preferably I to 4 r-^.v.^^ . y-ouo naving 1 to
provided. "-'^^^^^^ otherwise
.oT =° ^^^^^^ ^ ^av.ng -
- 20 caroon atoms, unless otherwise provided '
suitable "lower alkyl" and "lower alkvl moietV . r
--ins ar, lower, al Kyi.., "lower al toxy , lower . al .. and
"heterocyclic (lower, al.yl.. „ay include st-a cht K
one havin, 1 to e carbon ato.,s,, such a th i eth"r"'
propyl, rsopropyl, butyl, .sobutyl, sec-butyr^;;r:::-:;i ,
wo 96/10559
PCT/JP95/01982
- 12 -
pentyl, tert-pentyl, hexyl, and the like, and in which more
preferable example may be C^-C^ alkyl.
Suitable "lower aikylene" may include straight or
branched one such as methylene, ethylene, trimethylene ,
5 tetramethylene, pentamethylene, hexaraethylene,
methylmethylene, ethylethylene, propylene, and the like, in
which more preferable example may be C-^-C^^ aikylene ana the
most preferable one may be m.ethylene .
Suitable "lower alkoxy" and "lower alkoxy m.oiety" in
10 the zerm "lower alkoxy ( lower ) alkyl " may include methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentyloxy, c-pentyloxy, hexyloxy and the like.
Suitable "cycloalkyl" may include cyclo (C3-C7 ) alkyl
(e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
15 etc-) and the like.
Suitable "aryl" and "aryl moiety" in the term
"ar (lower) alkyl" may include phenyl, naphthyl and the like.
Suitable "halogen" may include fluorine, bromine,
chlorine and iodine.
20 Suitable "leaving group" may include acid residue, and
the like.
Suitable "acid residue" may include halogen as
exemplified above, and the like.
Suitable "heterocylic group" and "heterocyclic moiety"
25 in the term "heterocyclic ( lower ) alkyl " may include
unsaturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing 1 to 4 nitrogen
atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,
pyrazolyl, pyridyl, dihydropyridyl , pyrimidinyl, pyrazinyl,
30 pyridazinyl, triazolyl (e.g., lH-1 , 2 , 4-triazolyl , 4K-1,2,4-
triazolyl, lK-1 , 2, 3-triazolyl, 2H-1 , 2 , 3-triazolyl , etc.),
tetrazolyl (e.g., IH-tetrazolyl , 2K-tetrazolyl , etc.),
etc. ;
saturated 3 to 8-membered (more preferably 5 or 6-
35 membered) heteromonocyclic group containing 1 to 4 nitrogen
wo 96/10559
PCT/JP95/01982
- 13 -
atom(s), for example, pyrrol.dxnyl , xm.dazol .dxry ^
piperidyl, piperazinyl, etc.; '
unsaturated condensed h^terocyclxc group conta.nxna 1
to 4 nxtrogen ato.(s), for example, xndolvl, xso^ndol-
xndolinyl, indolizinyl, benz...dazolvl, .i.^ol^l ' '
isoquinolyl, indazolyl, benzotr iazol vl e^c • '
xnen^ ^^^^^^"^^^^^ ' 8-.e:nbered (.ore prefe^ablv 5 or 6-
mexnbered) heteromonocyclic grouo contaxning i o
atom(s) and 1 ^ r.,-^ oxygen
^ ana _ 3 nitrogen atomfs), fo^ ex^mr.!^
isnx;:. 7r^i wi ^- example, oxazolyl,
l.o.azolyl, oxadlazolyl (e.g., 1 , 2 , .-oxadiazolyl , 13,
oxadiazolyl, 1. 2, s-oxadiazclyl, ere.,, etc ■ '
saturated 3 to 8-membered (more preferabiv 5 or 5-
.e^ered, heteromonocyclic group containing I , °
ato.,s) and i .0 3 nitrogen ato.,3,, _.cr exaMo-e,"
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group contain.. g i
to 2 oxygen ato.,s, and 1 to 3 nitrogen ato„,a,,
example, benzoxazolyl, benzoxadiazolvl , et- ■
unsaturated 3 to 8-meMbered (more preferably . o- e-
mem^ered, heteromonocyclic .roup containing , ro 2~su:.ur
a.om.s, and 1 to 3 nitrogen atcm.s), for exa.mple
t-niazolyl, isothrazolyl, thiadlazoiyi (e g , ,\
thiadiazolyl, 1,2,4-thiadrazolyl, 1. 3, ^-th.Id.'Iz'^Iy^
1,^,5-thiadiazolyl, etc.), dihydrothiazinyl , etc ■
saturated 3 to 8-membered (more preferably 5 'or c-
n-embered, heteromonocyclic group containing , to o s-^f,,,
atom,s, and 1 to 3 nitrogen atom(s,, for examole, ' ^
thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferabiv 5 o>- 6-
membered) heteromonocyclic group contaxn.ng 1 to", su^-'u^
atom(s), for example, thienyl, dxhydrodithixnvl ~ ~
dxhydrodithionyl, etc.; ' '
unsaturated condensed heterocyclxc grouo conra^.^^g .
to . sulfur atom(s) and 1 to 3 nxcrogen atom"(s;, fo^'" '
example, benzothiazolyl , benzothiadiazolyl e- ■
PCT/JP95/01982
WO 96/10559
- 14 -
unsaturated 3 to S-membered {more preferably 5 or 6-
membered) heteromonocyclic group containing an oxygen atom,
for example, furyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-
5 membered) heteromonocyclic group containing an oxygen atom,
for example, 4H-2 , 3 , 5, 6-tetrahydropyranyl , etc . ;
unsaturated condensed heterocyclic group containing 1
to 3 oxygen atom(s), for example, chrom.anyl, isochromanyl ,
methylenedioxyphenyl, etc.;
10 unsaturated 3 to 8-membered (more preferably 5 or 6-
membered) heteromonocyclic group containing an oxygen atom
and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl ,
etc . ;
unsaturated condensed heterocyclic group containing 1
15 to 2 sulfur atom(s), for example, benzothienyl ,
benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an
oxygen atom and 1 to 2 sulfur atom(s), for example,
benzoxathiinyl , etc.; and the like.
20 Suitable "protected amino" may include acylamino or an
amino group substituted by a conventional protecting group
such as mono (or di or t ri ) aryl ( lower ) al kyl , for example,
mono (or di or tri ) phenyl ( lower ) al kyl (e.g., benzyl, trityi,
etc.) or the like.
25 Suitable "hydroxy protective group" in the term
"protected hydroxy" may include acyl, mono (or di or
tri ) phenyl ( lower ) alkyl which may have one or more suitable
substituent (s) (e.g., benzyl, 4-methoxybenzyl , trityi,
etc.), trisubstituted silyl [e.g., tri ( lower ) alkylsilyl
30 (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), et
substituted (lower) alkyl (e.g., methoxymethyl ,
ethoxymethyl , etc.), tetrahydropyranyl and the like.
1
Suitable "acyl" and "acyl moiety" in the term
35 "acylamino" may include
wo 96/10559
PCT/JP95/01982
- 15 -
Carbamoyl; Thiocarbamovl ;
Aliphatic acyl such aa'lower or hig.er al.anoy^ ,e g
for.yl, acetyl, propanoyl, butanoyi, 2-.ethyip,onanoW
pentanoy:, 2, 2-di.ethylp.opancy., hexanoyl, heptanoyT
tridecanoyl, tetradecanoyl, pentadecanoV hexad»/ ■
heptadeca^oy. octadeca„oy. . ncnadecan.;:'
lower or higher al.oxycar.onyl ,e.g., ..ethoxycar.o.vl
ethoxycar.cnyl , t-hutoxycar.onyi , t-per.tyloxvcar.onyl
heptyloxycarbonyl, etc.); ' ^aonyi,
lower or higher aX.ylsnlionyl (e.g., .ethylsulfonyl
ethylsulfonyl, etc.); ^^onyi,
lower or higher al..o:ysuifo„yi ,e.g., .ethoxy..l,onvi
=t.hoxysulronyi, etc.,; cycle Uower, ai.yXcarhonyl ,e g
cyclopentylcarbonyl, cyclohexylcar.onyl ,
.Aromatic acyl such as
"oyl (e.g., benzoyl, toluoyl, naohthoyl etc )•
ar (lower, alkanoyl ,e.g., .nhenyl (lower, al.anoyl ',
Phenylacetyl, phenylpropanoyl , phenvlbutanovl
Phenylisobutanoyl, Phe.nylpentanoyi , phe.nvlh^anoy. et- ■
naphthyl, lower, alkanoyl (e.g., naohtnylacetyl
naphthylpropanoyl, naphthylbutanovl, etc ) etc
ar (lower, al.enoyl [e.g.. Phenyl dower, al.enov,
.onenylpropenoyl, phenylbutenoyl , phenyl.ethacr'vlo;
Phenylpentenoyl, phenyl hexenovl , etc I "
naphthyl (lower, al,cenoyl (e.g., naphthvlorooe^ovl
naphthylbutenoyl, etc.), etc J- " '
ar (lower, al.oxyoarbonyl ' (e.g.'; 'pbenyl (lower, al.oxycarbony-
(e.g., benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl
naphthyloxycarbonyl, etc.);
aryloxy (lower) alkanoyl (e.g., phe.n.oxyacet vl ,
phenoxypropionyl, etc.);
e
wo 96/10559
PCT/JP95/01982
- 16 -
arylglyoxyloyl (e.g., phenylglyoxyloyl , naphrhylglyoxyloyl,
etc. ) ;
arylsulfonyl (e.g., phenylsul f onyl , p-tolylsulf onyl, etc.);
or the like.
5
Suitable " substi tuent " in the terms "aryl which may
have suitable subs ti tuent ( s ) " and "ar ( lower ) al kyl which may
have suitable substi tuent ( s ) " may include lower alkyl as
exemclified above, lower alkoxy as exemplified above, lower
10 alkenyl, lower alkynyl, mono (or di or tri ) halo ( lower ) al kyl
wherein halogen moiety and lower alkyl moiety are each as
exemplified above, cyclo { lower ) alkyl , cyclo ( lower ) alkenyl ,
halogen as exemplified above, carboxy, protected carboxy,
hydroxy, protected hydroxy, aryl as exemplified above,
15 ar ( lower ) alkyl wherein aryl moiety and lower alkyl moiety
are each as e.xemplified above, carboxy (lower ) alkyl wherein
lower alkyl moiety as exemplified above, protected
carboxy ( lower ) alkyl, nitro, amino, protected amino,
di ( lower ) alkylamino wherein lower alkyl moiety is as
20 exemplified above, amino ( lower ) alkyl wherein lower alkyl
moiety is as exem.plified above, protected
amino ( lower ) al kyl , hydroxy ( lower ) alkyl wherein lower alkyl
moiety is as exemplified above, protected
hydroxy { lower) alkyl, cyano, sulfc, sulfam.oyl, carbamoyloxy ,
25 mercapto, lower alkylthio wherein lower alkyl moiety is as
exem.plified above, imino, protected amino as exemplified
above, heterocyclic group which m.ay have mono (or di or
tri ) ar ( lower ) alkyl wherein heterocyclic group, aryl moiety
and lower alkyl moiety are each as exemplified above, and
30 Che like.
Suitable "substituent" in the cerm "heterocyclic group
v^rhich may have suitable subs titueni: ( s ^ " may include lower
alkyl as exemplified above, lower alkoxy as exemplified
above, lower alkenyl, lower alkynyl, mono (or di or
'35 tri) halo (lower) alkyl wherein halogen moiety and lower alkyl
wo 96/10559
PCT/JP95/01982
- 17 -
moiety are each as exemplified aoove, cyclo ( lower ) alkyl ,
cyclo (lower) alkenyl, halogen as exemplified above, carbox
orocected carboxy, hydroxy, projected hydroxy, as
exemplified above, aryi as exemplified above, monoior di c
tri) ar (lower) alkyl wherein aryl moiery and lower alxvl
moiery are each as exemplified above, carboxy ( lower ) alkyl
wherein lower alkyl moiety as exemplified above, protectee
carboxy (lower) alkyl, nitro, amino, protectee amino,
di (lower) alkylam.ino wherein lower alkyl rr.oiery is as
exemplified above, amino (lower ) alkyl wherein lower alkyl
moiery is as exemplified above, projected amino (lower) -
alkyl, hydroxy (lower) alkyl wherein lower alkyl moiety is a
exemplified above, protected hydroxy { lower ) alkyl , cvanc,
sulfo, sulfam.oyl, carbamoyloxy, mercapto, lower alkylthio
wherein lower alkyl moiety is as exemplified above, lower
aikylsulfinyl wherein lower alkyl moiety is as exemplified
above, acyl as exemplified above, oxo, imino, and the like.
Suitable "subs tituent " in the term "thiazolyl,
imidazolyl, pyrazolyl, pyridyl, thienyl, furyl or
isoxazolyl, each of which may have suitable subst i tuent ( s ) "
may include lower alkyl as exemplified above, lower aikoxy
as exemplified above, lower alkenyl, lower alkynyl, mono (or
di or tri)halo (lower) alkyl wherein halogen m.oiety and lower
alkyl moiety are each as exemplified above,
cyclo (lower) alkyl, cyclo ( lower ) alkenyl , halogen as
exemplified above, carboxy, protected carboxy, hydroxy,
protected hydroxy, aryl as exemplified above, haloaryl
wherein halogen moiety and aryl moiety are each as
exem.plified above, arylthio wherein aryl moiety is as
exem.plified above, heterocyclic group as exem.plified aoove,
ar (lower) alkyl wherein aryl moiety and lov/er alkyl moiety
are each as exemplified above, carboxy ( lower ; alkyl wherein
lower alkyl moiety as exemplified above, protected
carboxy (lower) alkyl, nitro, amino, protected amdno,
di (lower) alkylamino wherein lower alkyl moiety is as
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PCT/JP95/01982
- 18 -
exemplified above, amino ( lower ) alkyl wherein lower alkyl
moiety is as exemplified above, protected
amino ( lower ) al kyl , hydroxy (lower) alkyl wherein lower alkyl
moiety is as exemplified above, protected
5 hydroxy ( lower) alkyl, cyano, sulfo, sulfamoyl, carbamoyloxy,
mercapto, lower alkylthio wherein lower alkyl moiety is as
exemplified above, imino, and the like.
The processes for preparing the object and starting
10 com.pounds of the present invention are explained in detail
in the following.
Process (JJ_
The compound (I) or a salt thereof can be prepared by
15 reacting the compound (II) or a salt thereof with the
compound (III) or a salt thereof.
This reaction is usually carried out in a solvent such
as water, alcohol (e.g., methanol, ethanol, etc.), benzene,
N, N-dimethylf ormamide, tetrahydrof uran, toluene, methylene
2C chloride, ethylene dichloride, chloroform, dioxane, diethyl
ether or any other solvents which do not adversely affect
the reaction, or the mixture thereof.
The reaction temperature is not critical and the
reaction is usually carried out under cooling to warming.
25 When the starting compound is in liquid, it can be
used also as a solvent.
Process i2±
The compound (I) or a salt thereof can be prepared by
30 subjecting the compound (II) or a salt thereof and the
compound (IV) or a salt thereof to formation reaction of
ureido group.
This reaction is carried out in the presence of
reagent which introduces carbonyl group such as phosgene
35 [e.g. , triphosgene, etc.], haloformate compound [e.g.
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PCT/JP95/01982
- 19 -
10
30
athyl chlorofor^ate, trichloromethyl chlorof or„ate. ohenyl
chlorof=™ate, etc.], N, -carbonyldli„ida.ole, „eta'.
carbonyl compounds O.g. cobalt carbonyl, .ancanese "
carbonyl, etc.,, a combination of carbon monoxide and
catalysts such as palladium chloride, etc., or the lijce
„at::,^ ::l"°^e";,^:e^^::::^t:::;^:/^:"
^. .-...ethyl.ormamide. tetrahydro.ran, tl^] ' i:::^:
chlor.de, ethylene dichloride, chloroform, dioxane, drethyl
etner or any other solvents which do not adversely affect
the reaction, or the mixture thereof.
The reaction temperature is not critical and the
reaction is usually carried out under cooling to heating
The reaction is usually carried out in the prese.nce'o.
an organrc base such as tri , lower) al.ylamine ,e g
tr.methylamine, triethylamine, dirsopropylethvlamine
etc. ) , or the like.
:)ce.s.s
3,^-,''" "~ " ^ ^•'"-^ can be prepared bv
suo.ec.xng the compound ,Ia, or a salt thereof to ox-dat<o:
reaction.
oxldatron is carried out in a conventional manner,
whrch rs capable or oxidizing a sulfur atom to an ox.d. zed
" ^"""-^ -^-"^^^ -i^^i^in. "agent mav be oxv^e
acxd such as periodate ,e.g. sodium, Perrodate, Potassium"
periodate, etc.), peroxy acid such as perbenzoic acd
the'u.e"^""'' acfd. eto, and
The reaction is usually carried out rn a conventiora-
solvent such as water, alcohol, ,e.g., methanol, ethanol, "
isopropyl alcohol, etc.,, tetrahydroiuran, dioxane
dichloromethane, ethylene dichloride, chloroform v n
drmethylformamide, N, N-dimethyiacetamide, or anv other
organic solvent which does not adversely affect'the
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PCT/JP95/01982
- 20 -
10
15
20
25
30
react ion .
Among these solvents, hydrophilic solvents may be used
in a mixture with water.
The reaction temperature is not critical and the
reaction is usually carried ouc under cooling to heating.
The compound (VII) or a salt thereof can be prepared
by reacting the compound (V) with the compound (VI) .
The reaction can be carried out in the manner
disclosed in Preparation 2 or similar manners rhereto.
The compound (IXa) or a salt rhereof can be prepared
by reacting the compound (VII) or a salt thereof with the
compound (VIII) or a salt thereof.
The reaction can be carried out in the manner
disclosed in Preparation 20 cr similar manners thereuo .
Process [£1
The compound (X) or a salt thereof can be prepared by
subjecting the compound (IX) or a salt thereof to reduction
reaction .
Reduction is carried out m a conventional manner,
including chemical reduction and catalytic reduction.
Suitable reducing reagents to be used in chemical
reduction and hydrides (e.g., hydrogen iodide, hydrogen
sulfide, lithium aluminum hydride, sodium borohydride,
sodium, cyanoborohydride, aiisobutylaluminum hydride, ere.),
a m.etal (e.g., tin, zinc, iron, etc.) or metallic compound
(e.g., chromium chloride, chromium acetate, etc.), and the
like .
Suitable catalysts to be used in catalytic reduction
are conventional ones such as platinum, catalysts (e.g.,
platinum plate, spongy platinum, platinum black, colloidal
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PCT/JP95/01982
- 21 -
Plarinum, plat.num oxide, platinum wire, etc ) n. ^ i -•
ca alys.s (e.g., spongy pallad.u., pallad.uxn blaC,
palladium oxide, palladium on caroon, colloidal n. 1 •■
palladium on barium sulf.^. ^°^^°-dal pallaaium,
5 etc ) n.ck., P-Haaaum on barium carbonate,
oxxd ' R ^^^^^^^^^ -^uced nxc.el, nxc.el
oxxde, Ranev nickel (=-i-r- \ ^ ^
reduction is usually carried out i the
conventional solvent such as water, alcoho" '(e ,
methanol, ethanol, orooanol ot,- i ► ^ .
^ , -ropanol, etc. I, tetrahydrofuran,
toluene, dichloro.ethane, dioxane, N,N-diMethvlfor» ■
«.N-di„ethylaceta.ide or any other solvents „ 1 .rr'
adversely affect the reaction, or a .,.„ure thereof
The reduction is usually carried out xn the presence
Of an organic acid or an inorganic acid ,e a f
acetic acid, propionrc acid, tr.fluoroacir'c Icrd
L"L°,'":t:T "^^^^-^^"^^ hydro.:o..c
2C
25
to be'u'sidT"'' . a.ove-.entioned ac.ds
be used m cnemical reduction are ^n Tic.^'w
1 , -.1 -Liquid, tnev r = ^
also be used as a solvent.
The compound (Xa) or a salt thereof can
wi th the
la (All) or a salt thereof.
rf^^nr-ir^r. +-K ^ """"^""^ ^^^^ prepared by
reacting the compound (XI) or a salt thereof
compound (XII) or a salt thereof.
The reaction can be carried out in the manner
disclosed m Preparation 48 or similar manners theret
:oce?;<:; (P)
reacting th"' ^ -V
reacting the compound (XIII) or a salt thereof with ^he '
compound (XII) or a salt thereof.
The reaction can be carried out m the manner
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PCT/JP95/01982
- 22 -
disclosed in Preparation 38 or similar manners thereto.
Process LEI
The compound (Ila) or a salr thereof can be prepared
5 by reacting the compound (X) or a salt thereof with the
compound (XIV) or a salt thereof and then by subjecting the
resultant compound to reduction reaction.
Reduction is carried out in a conventional manner,
including chemical reduction and catalytic reduction.
10 Suitable reducing reagent to be used in chemical
reduction are hydrides {e.g., hydrogen iodide, hydrogen
sulfide, lithium aluminum hydride, sodimn borohydride,
sodium cyanoborohydride, etc.) or a combination of a metal
(e.g., tin, zinc, iron, etc.) or metallic compound (e.g.,
15 chromium chloride, chromium acetate, etc.) and an organic
acid or an inorganic acid (e.g., formic acid, acetic acid,
propionic acid, trif luoroacetic acid,
p-toluenesulf onic acid, hydrochloric acid, hydrobromic
acid, etc . ) .
20 Suitable catalysts to be used in catalytic reducrion
are conventional ones such as platinum catalysts (e.g.,
platinum plate, spongy platinum, platinum black, colloidal
platinum, platinum oxide, platinum wire, etc.), palladium
catalysts (e.g., spongy palladium, palladium black,
25 palladium oxide, palladium on carbon, colloidal palladium,
palladium on barium sulfate, palladium on barium carbonate,
etc.), nickel catalysts (e.g., reduced nickel, nickel
oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced
cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced
30 iron, Raney iron, Ullman iron, etc.), and the like.
The reduction is usually carried out in a conventional
solvent such as water, alcohol (e.g., methanol, ethanol,
propanol, etc.), tetrahydrof uran, toluene, dioxane,
N, N-dimethyl f ormamide , N, N-dimethylacetamide or any other
35 solvents which do not adversely affect the reaction, or a
PCT/JP95/01982
- 23 -
mixture thereof.
also be used as a solvent. ^ ' "'"^
Suitable salts of the object and
Processes (li ^ starting compounds i
ocesse. (l)-(3, and (A) - (E) can be referred to
as exemplified for the cor.pound ,1,
isolate! """""""^ ' can be
isolated ana purified by a conventional method such as
pulverization, recrvs^;, i i ^ ^ = ^ ■ ^ucnas
reprecicitaf ^^luntn chromatography,
reprecipitation, or the like.
It is to be noted that the coiuDound (t) ^^d rh. ^-
compounds ma. include one or „ore stereoii^Ie 3, ^ ch^l"
optical isomer.s, and geometrical isomer.s, due to
asv^etric carbon ato„,s, and double bond.s,, and all o.
su^h isomers and mixture thereof • .
scope of this invention. ' '^^^
as fonot"" - -lect compound a, are
is a group of the formula :
r4
in which
is phenyl which may have 1 to 3 suitable
substituent(s) (more preferably substi^uent
selected from the group consisting of haloge^
ower alkyl, di ( lower ) alX-ylammo, protected ^^..o
(more preferably acylamino;
-St preferably lower alkylsulfonylamino; , cyano
heterocyclic group (more preferably tetrazolyl) '
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PCT/JP95/01982
- 24 -
which may have nono (or di or tri ) ar ( lower ) alkyl
(more preferably mono (or di or
tri) phenyK lower) alkyl; most preferably
triphenyl (lov/er) alkyl) , hydroxy, protected
hydroxy (more preferably lower
alkoxy (lower) alkoxy) ana mono (or di or
tri) halo (lower) alkyl (more preferably
trihalo (lower) alkyi) ) , [more preferably phenyl,
halophenyl, lower alkylphenyl,
di (lower) alkylaminophenyl, lower
alkylsulf onylam-inophenyl , cyanophenyl,
tetrazolylphenyi, (triphenyl (lower) -
alkyltetrazolyl) phenyl, trihalo (lower) -
alkylphenyl, phenyl having two lower alkyl and
hydroxy, or phenyl having two lower alkyl and
lower alkoxy (lower) alkoxy] ; or heterocyclic group
(more preferably thienyl, pyrazolyl, imidazolyl,
triazolyl, pyridyl, pyrrolyl, tetrazolyl,
oxazolyl, thiazolyi, oxadiazolyl, piperazinyl,
rhiazolidinyl or methylenedioxypheny 1 ) which m.ay
have 1 to 3 (more preferably one or two) suitable
substituent (s) (more preferably substituent
selected from the group consisting of lower
alkyl, mono (or di or tri ) ar ( lower ) alkyl (more
preferably phenyl ( lower ) alkyl or
triphenyl (lower alkyl) and oxo) [more preferably
thienvl; pyrazolyl which may have lower alkyl or
rriphenyl (lower) alkyl; imidazolyl;
rriazolyl which may have one or two
substituent (s) selected from the group consisting
of lower alkyl and phenyl ( lower ) alkyl ; pyridyl;
pyrrolyl; tetrazolyl which may have lower alkyl
or triphenyl (lower) alkyl; oxazolyl;
lower alkylthiazolyl; lower alkyloxadiazolyl ;
lower alkylpiperazinyl; dioxothiazolidinyl ; or
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PCT/JP95/01982
10
15
- 25 -
methyl enedioxyphenylj ;
■35
^ is bond, lower alkylene, -s-, -o-, -|- ==c"-
-CONH-, -N-CO- (in which R ' ^- i' ' - '
J wnicn R IS lower alkyl),
-NHS02-, -SO2NH-, -SO2NHCO- or -CONHSO,-,;
suL^ / =ubstituent,s, ,„ore preferably
1 wer al .v., ^^^^^ J
preferably acyloxy, , phenyl, halophenyl, p.enylt.,o
and pyrrolyl, [„ore preferably haloohenylthlazolvl
Phe.yU„i.azolyl, phenylpyrazolyl, phenyl.yrrd;:
Phanylthlopyrldyl, pyrrolyXpyr.CyX , phenyiL e„ I
Phenylfuryl, p.enyli^oxa.oXyl or chro„anvl .al
lower alkyl and hydroxy]; ' '
" aitoxyllowerlalkvi,
=yclo (C3-c„ alkyl ,„ore preferably c^clopentyl,
cyclohexyl or cycloheptyl , , phenyl , lower, alkyl wh.C
™ay nave 1 to 3 ,„ore preferably one or two-
Tf 3Ultable sub.trtuent.s ,.ore
^"'"""-^ substrtnent.s, selected fro. the group
consisting of halogen, lower alkoxy and d. (lower
alkyl, a^rno, Uore preferably Phenyl dower, alkyl
halophenyl, lower, alkyl. lower alkoxyphenyl .lower alky,
or or (lower alkyl, aminophenyl (lower, ai ky-J
tetrahydropyranyl or furyl (lower, alkvl, and
.3 Phenyl whi.h .ay have 1 to 3 (.ore preferable two o-
three, suitable substituent ,s , (.ore preferably
substituent selected fro. the group consrst^n^ o'
iower alkyl and halogen, Core preferably di'o- '
tri, (lower alkyllphenyl or trihalcphenyl J ■
pyrldyl or pyri.idlnyl , eaoh of which .ay'have 1 to 3
30 r:
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PCT/JP95/01982
- 26 -
(more preferably two or three) suitable subs ti tuent ( s )
(more preferably substituent selected from the group
consisting of lower alkyl, lower alkylthio, halogen,
lower alkoxy, lower alkylsulf inyl and lower
5 alkylsulfonyl ) [more preferably pyridyl having two
lower alkylthio and lower alkyl;
pyridyl having halogen, lower alkyl and lower
alkylthio; tri (lower alkyl ) pyridyl ; pyridyl having two
( lower ) alkoxy and lower alkyl; pyridyl having lower
10 alkoxy, lower alkylrhio and lower alkyl; pyridyl
having two lower alkylsulf inyl and lower alkyl;
pyridyl having two lower alkylsulfonyl and lower
alkyl; pyridyl having lower alkylthio, lower alkoxy
and lower alkyl; pyridyl having lower al kylsul f inyl ,
"15 lower alkylsulfonyl and lower alkyl; pyridyl having
lower alkylthio, lower alkylsulfonyl and lower alkyl;
pyridyl having two halogen and lower alkyl;
di ( lower ) alkoxypyrimidinyl ; or pyrimidinyl having two
lower alkyluhio and lower alkylj, and
20 n is 0 or 1.
The object compounds (I) and pharmaceutically
acceptable salts thereof possess a strong inhibitory
activity against ACAT, and are useful for the prevention
25 and/or treatment of hypercholesterolemia, hyperlipidemia,
atherosclerosis or diseases caused thereby.
In order to illustrate the usefulness of the object
compound (I), the pharmacological test data of the
30 representative compound of the compound (I) are shown in
the following.
35
Test compound (a) :
1-Cycloheptyl-l- ( 4-phenoxyphenylmethyl ) -3- (2,4,6-
trif luorophenyl ) urea
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Test ;
Acyl-CoA : cholesterol acyl transferase (ACAT)
inhibitory activity
5 Method :
ACAT activity was measured by the method of Heidar et
al. described in Journal of Lipid Research. Vol. 24 pace
.127 ,1.83,. The enzyme ACAT was prepared fron the mLosal
..crosome fraction of the small r.test.ne of male, iL: e '
old uapanese white rabbits which had been fed diet
containing 2. cholesterol for 8 weefe. The inhibitory
activity of test compound was calculated by measuring the
a.mou„t Of the labeled cholesterol ester produced from '
IV o "';"'"'' Cholesterol as follows.
( CJOleoyl-CoA and microsome were incubated w<th test
oy the addition of chlorof orm-methanol (2-. v/V)
Cholesterol ester fraction in the chloroform-methano.
c'urtertr' thin-layer chromatography and was
counted their label.
20
Result :
25
Test Compound
IC50 (M)
(a)
1.1 X 10-8
30
35
For therapeutic purpose, the compound (t, of the
Presen. invention can be used in a form of oharmaceut ^ c^ 1
preparation containing one of said compounds, as ar ac'-Ive
angredienr, m admixture with a pharmaceutical! v acceot^abl^
carrier such as an organic or inorganic solid o^ liau'.n
excipient suitable for oral, parenteral or externa^ ' "
(topical) administration, wherein more preferable one is
oral administration. The pharmaceutical preparations mav
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PCT/JP95/01982
- 28 -
be capsules, tablets, dragees, granules, suppositories,
solution, lotion, suspension, emulsion, ointment, gel, or
the like. If desired, there may be included in these
preparations, auxiliary substances, stabilizing agents,
5 wetting or emulsifying agents, buffers and other commonly
used additives.
While the dosage of the compound (I) will vary
depending upon the age and condition of the patient, an
average single dose of about 0.1 mg, 1 mg, 10 mg, 50 ng,
10 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may
be effective for treating the above-mentioned diseases. In
general, amounts between 0.1 mg/body and about 1,000
mg/body may be administered per day.
15 The following Preparations and Examples are given for
the purpose of illustrating the present invention in more
detail .
20
- to be continued on the next page -
25
30
35
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- 29 -
To a solution of acetophenone (^o a) ^nH w
added so..u„ ^ -
The mixture was stirred for one hou- at ro ''^ " ° ^
then heated for 30 .in.tes at Jc :
reaction fixture was added 2..N-hvdroth L r;"/',-'"
and extracted with ethyl acetate.' The or"^- i
washed With water, .rine. dried over .a^nes ' 1^ 1^1^
evaporated in vacuo y^esium sulrate,
s.l^ca gel (700 - chro.atographed on
^ ^ °° ^' ^-^---ne - ethyl acetate (4:1 to lo,,
to g.ve .ethyl 2 , 4-dioxo-4-phenylbutyrate (.0 32 g
^^"^^ ^ ^^^2' ^^0^' 157., 14:4; 126;^n-I
NMR (CDCl-,, 5) • 3 OS , ,
^-68 (3H, m), 7.95-8.06 (2H, m) is n 1- c
^ ' ' 15.0-1O.5 (IH,
APCI-MASS (m/z) : 207 (M+H+)
The mixture of S-acetylbenzonxtrile • (43 ^5
d..ethylfor.a..de d.methyl acetal (107.. ^
for 3 hours under nitrogen. .he ..xt'ure .as ^^^^^
concentrated in vacuo and diisopropyl ether (400 .1 )
hv fii^ V - i-xt.ciLes were collected
by fxltratxon, washed wxth diisooropvl ether and H ■
aivf= ^-r/T7i ■:, ^- " festner and dried to
9^ve 3 [(0-3-drn,ethylaminopropenoylJbenzonitriie ,48.62
(KBr, : 3070, 2900, 2225, 16.5, 1600, 1550 c^"!
s ,
NMR (DMSO-d„ 6) : 2.96 (3H, s), 3.17 nH
5-93 (IH, d, J=12.1HZ), 7.65 (IH, dd/j^^ .
7.72 (IH, d, J=12.1Hz), 7.95 (IK ' d'
J=7.7Hz), 8.20 (IH, d, J=7.7Hz), 8.3. ( IH '
APCI-MASS (m/z) : 201 (.M+H+) - < s
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PCT/JP95/01982
10
- 30 -
Preparation ?
To a solution of N- ( 3-acetylbenzyl ) -acetamide (9.56 g)
in 1, 2-dimethoxyethane (150 mi) was added dropwise broniine
(7.99 g) at room temperature and the mixture was stirred at
the same temperature for 1.5 hours. The precipitates were
dissolved by addition of echanol (150 ml) and thioacetamide
(4.51 g) was added to the solution. The mixture was
refluxed for 2.5 hours and evaporated in vacuo. The
residue was extracted by ethyl acetate and the organic
layer was washed with water and brine, dried over magnesium
sulfate and evaporated in vacuo. The residue was purified
by column chromatography on silica gel to give N- [ (2-
methylthia2ol-4-yl) benzyl] -acetamide (8.24 g) .
IR (KBr) : 3295, 3110, 3070, 2930, 1645, 1550 cm"-
^5 NMR (DMSO-dg, 5) : 1.89 (3K, s), 2.72 (3H, s),
4.29 (2H, d, J=5.9Hz), 7.2-7.9 (4K, m) , 7.90 (IK,
s), 8.4 0 (IH, t, J=5.9Hz)
APCI-MASS (m/z) : 2 47 (M+H"^)
2 0 Preparation 4
To a solution of N- [ 3- (2-methylthiazol-4-yl ) benzvl j -
aceta.'nide (8.23 g) in ethanol (100 ml) was added cone.
Hydrochloric acid (13.9 m.l ) and the mixture was refluxed
for 12 hours. The mixture was cooled to 5°C and acetone
25 (100 ml) was added thereto slowly. The precipitates were
collected by filtration and washed with acetone, dried over
phosphorus pentoxide to give 3- (2-methylthiazol-4-yl ) -
benzylamine-hydrochloride (5.14 g) .
IR (KBr) : 3090, 2915, 2840, 2635, 1605, 1575,
30 1510 cm"-
NMR (DMSO-dg, 5) : 2.7 3 (3H, s), 4.07 ,;2H, B.Bq,
J=5.7Hz), 7.47 {2H, d, J=5.1.H2), 7.9-8.0 (IH, rr.) ,
7.97 (IH, s), 8.14 (IH, s), 8.57 (2H, br s)
APCI-MASS (m/z) : 20 5 (M of free compound +H"^)
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PCT/JP95/01982
- 31 -
To a suspension of methyl h-
propenoyljbenzoate 'Sn > ■'~^^"»ethyiamno-
-etic .... ,,.3, '^^0 was ...ed
-te. , iirrr::"^ -no....... ,,.3, ^^^^
solvent ..3 evaporate, .n l «- t.e
"•^"^■^aLea m vacuo t!-,«
" et.yx acetate. „a3he. ..th .aterir:;^"^
-^nesiu. sulfate, evaporated in va'cuo t
(pyrazol-3-yl,benzoate (4 21 , """^ "^"^^
- 'KBr, : 3300-3500 ;.r, „os. ..,0,
N«R <DMSO-d„ 5, : 3.S6 <3„, 3;, s S5
Franariti -n r
To a solution of methyl 4-r(f,_, ^.
propenoyljbenzoate (523 , ■ '^■^"ethyla.^ino-
added methylhydrazine',1 31
3 hours at roo„ te.neratur ^ ^o t^""" "^-'""^
5N-sodiu.. hydroxide solution in 'order
-olrng and extracted „ith ethyl a^e at
layer was washed with saturarl
solution, wate. br, bicarbonate
-.oorated in ;:c:o "^fn^"^^ ,
<ei trn ith -ohioroLiirr:: r^v;,
-3- (l-niechylpyra2oT-3-vl IK (--^C..!)), methyl
sr^jf a^u^ J yl)ben2oate f3 id ^>
methyl — ethylpyrazol-5-yl,ben o te a":: """^^
Obtained. ^a^e (x.63 g) was
Methyl -U-.ethylpyrazol-3-yl,benzoate-
^ i-eTc^r • 13.,
'-CI3, 5, : 3.« ,3„, s,, 3... ,3, s. ^ -
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- 52
7.93 (2H, IT.), 8.03-8.14 (2K, m)
APCI-MASS (m/z) : 217 (M+H^)
Methyl 4- (l-methylpyrazol-S-yDbenzoate :
5 IR (KBD : 3035, 2960, 1718, 1614, 1464, 1425,
1286 cm~l
NMR {CDCI3, 5) : 3.93 (3H, s), 3.96 (3H, s), 6.38
(IH, d, J=2.0Hz), -^.46-7.57 (2H, n:) , 7.54 (IH, d
J=2.0Hz), 8.08-8.19 f2.H, m)
^° APCI-MASS (m/z) : 217 m^'d'^ }
Tc a solution of thiophenol (2.20 g) m methanol (^0
ml) was added 28?, sodium methoxide-methanol solution (3.86
15 ml) and the mixture was stirred at room temperature for 15
minutes. To the mixture was added methyl 6-
chloronicotinate (3.43 g) and the mixture was refluxed for
6.5 hours under nitrogen. The mixture was evaporated to
dryness and the residue was extracted with ethvl acetate
20 The organic layer was washed with water a.nd brine, dried
over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
to give methyl 6- (phenyl thio ) nicotinate (5.13 g) as a
crystal .
fJ^Br) : 3070, 2950, 1720, 1585, 1550 cn-'-
NMR (CDCI3, 5) : 5.91 (3H, s), 6.86 (IH, dd, J=8.5,
0.8Hz), 7.4-7.5 (5H, m) , 7.55-7.7 (2H, m) , 3.00
(IH, dd, J=8.5, 2.2KZ), 9.00 (IH, dd, J=2.2,
0.8Hz)
APCI-MASS (m/z) : 24 6 (M+H+)
To a solution of aniline (8.20 g) in pyridine (100 ml)
was added portionwise 4-carboxybenzenesulf onyl chloride
35 (17.65 g) at 5°C and nhe mixture was stirred at SCc for 6
wo 96/10559
PCT/JP95/01982
- 33 -
con.. .v..cc..::.r:rr,;::i:r —
formed and collected bv ^ • i . ' P^^^ipitates were
the organic layer was'washed wi.^ tri"'' '^"""^^
magnesium sulfate ^nn i^rine, aried over
•^"xj-dce and evaporated -i -i
"as Obtained by filtration
-i- i> 5 cm -'■
i>JMR (DMSO-d., 5) . 7 0-70
O' ^/ • 1.0-1 9 /Q" ^,
m), 7 85 rPR w ^' '-2-7.35 (2H,
(2H, d, J=8.4Hz), 8 07 w
10.45 (IH ^' J=8.4Hz),
(IH, s)
'^o a solutTor nf ^ .
chlor.de ,8.83 g, a, 3^^'^" f ^enzenesulf onyl
roo. temperature for 1 I
poured rnto a :Lt„:"f":tt;^'-"'^"-
-ater ,100 :„l, ' ".''^^ ^"tate ,150 m1,,
P^crpltatea „ere forr^ aT L^eVbT ^ '
washed with ethvl =^ . ^-^ected oy filtration,
- ^ao.o o.er"::oVr::rp;::or:::°r^°^^^
'PW-yIsulfonyla.rno,be„.;:: 0%;°.""^ "^'^^
™^ filtrate „a. separated and the o'-glr " I "'"^ "'^^"^
brrne, dried o.er „agnesi™ T'^''
-cuo. xo the residue was added dr, o-^o:" T"""'
second orop ,3.83 g, „3s obtained by Tl:?^.^'"'" ^^'^
" '-r, : 3.30, 30VO. .„o, r.-^rLe :^■..3
1610, 1510 cm-1 '
* — • • /
PCT/JP95/01982
WO 96/10559
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q, J=7.1Hz), 7.22 {2H, d, J=8.8Hz), 7.5-7.7 {3H,
m) , 7.8-7.9 (4H, m) , 10.86 (IH, s)
APCI-MASS (m/z) : 30 6 (M-rH"^)
5 Preparation 10
To a stirred mixture of bromine (50.2 ml) in
dichloromethane (1 P) and anhydrous sodium carbonate (206.8
g) was added a solution of 1-methylpyrazole (80 g) in
dichloromethane (100 ml) at 0-5°C. After stirring for one
10 hour under ice-cooling, the mixture was stirred for further
one hour at room temperature, then cooled. To the reaction
mixture water (1 t) was added thereto. The dichloromethane
layer was separated and aqueous layer was extracted twice
with dichloromethane. The combined organic layer was
15 washed with water and brine, dried over magnesium sulfate
and evaporated under reduced pressure. The residue was
distilled in vacuo to afford 4-bromo-l-m.ethylpyrazole
( 150 . 6 g) .
bp : 82 "C (20 mmHg)
20 IR (Neat) : 3100, 2930 cn"^
NMR (CDC13, 5) : 3.89 (3H, s), 7.38 (IH, s),
7.44 ( 1 H , s )
APCI-MASS (m/z) : 161, 163 (M+H^)
2 5 Preparat ion 11
To a solution of methyl 4-formylbenzoate (4.0 gi and
tosylm.ethyl isocyanide (5.0 g) in methanol (40 ml) was
added potassium carbonate (3.54 g) . The mixture was
refluxed for 3.5 hours. After cooling, the reaction
30 mixture was diluted with ethyl acetate (300 ml), washed
with water and brine, dried over magnesium sulfate,
evaporated in vacuo. The residue was chromatographed on
silica gel (100 g, eluting with n-hexane - ethyl acetate
(2:1 to 1:1) to give methyl 4- (oxazol-5-yl) benzoate (4.04
35 g) .
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20
- 35 -
IR (KEr) :
1726, 1614, 1275, 1109 cm-1
<CDCX3, 5, : 3.9. <3H, s> , UH. s,
5 APCI-MASS (m/z) : 204 (M+K+!
Prgr.arat-,„p ]^
vacuo. To the residue was added chloroforn Th.
solution was washed with water, brine d^Ie^
sulfate, evaporat.H ' , ' ''^""^ magnesium
30
--^iit;, aried o
sulrate, evaporated in vacuo. The residue was
chroxnatographed on sil.ca gel aSO g, n-^exare .
acetate (3-1) i • . -^exane - ethyl
.'5.25 g) "'^^^ ^-^^^^----™v^-5-phenyl.3oxazole
IR (KBr) : 1728, 1570, 1448, 1250 cm-1 '
7:^^- ^ -01 3), 6.94 an, s),
7.^5-7.5:> (3H, m), 7.75-7.88 (2H, ml
APCI-MASS (m/z) : 204
A solution Of methyl 2, 4-dioxo-4-ohenylbutv^ate ^
and hydrazine, mono.hydrate (1 49 n,i , ^-'^"ty.ate (o g)
25 refluxed for 5 hou^s rl ^
Th« - solvent was removed m vacuo
The r n, ^olid was collected by f.l.rat.on, wa .ed
wxtn dx.sopropyl ether to gxve 5-methoxvlcarbonyl-3:
pyenylpyrazole (3.0 g) . ' ^
IH (KBr) : 2500-3400 (br) , 1730, 1491, i,,, ,,-1
NMR (DMSO-d^, 5) ■ 3 fl^ ,
6' - 3.83, 3.88 (total 3H, each s),
^•18-7.53 (4H, m), 7.78-7.9. (S'^' ^n) 13 .
(IH, m) ^'
APCI-MASS (m/2) : 203
35
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Preparation 14
A mixture of methyl 3-cyanobenzoate (8.0 g) , sodium
azide (19.38 g) and ammonium chloride (15.95 g) in N,N-
dimethylf ormamide (32 m.l) was heated for 2.5 hours at
5 12C°C. The mixture was poured into ice water (300 ml) -
ethyl acetate (100 ml) . Under ice cooling, to the solution
was added sodium nitrite (20.5 g) then
6N-hydrochloric acid until pH was adjusted to 1-2. After
stirring for 30 minutes at room temperature, the mixture
10 was extracted with ethyl acetate - tetrahydrof uran, washed
with water and brine, dried over magnesium sulfate,
evaporated- in vacuo to give methyl 3- ( lH-tetrazol-5-
yDbenzoate (10.01 g) .
IR (KBr) : 2300-3500 (br) , 1705, 1684, 1618,
• 15 1562 cm"-
NMR (DMS0-dg,5) : 3.93 (3H, s), 7.78 (IH, dd,
J='?.9, 7.9Hz), 8.10-8.20 (IH, m) , 8.25-8.38 (IH,
m) , 8. 60-8 . 70 (IK, m)
APCI-MASS (m/z) : 205 (M+H"^)
20
Preparat ion 15
To the solution of 4-bromobenzyl alcohol (4.85 g) and
3-tri-n-butylstannylthiophene (11.6 g) was added
tetrakis (triphenylphosphine) palladium(O) (0.9 g) , then the
25 mixture was heated for one hour at 140°C. After cooling,
the resulting precipitate was collected by filtration and
washed with n-hexane to give 4- ( 3- thienyl) benzyl alcohol
(2 . 67 g) .
IR (KBr) : 3300 (br) , 1425, 1200, 1045, 1014,
30 777 cm"^
NMR (CDCI3, 5) : 1.72 (IH, t, J=5.9Kz), 4.72 (2H, d,
J=5.9Hz), 7.30-7.50 (5H, m) , 7.60 (2H, dd, J=6.4,
1 . SHz)
35
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- 37 -
The following compound was obtained arr^o.--
similar manner to that of p ^ccoramg to a
L.O cnat or Preparation 15.
4-(2-Thienyl)ben2yl alcohol
IH (KBr) : 3300 (br) , 1,27, 1213, 1047 806 cm-
NMR (CDCI3, 5) • 1 70 r^- ^ ' 806 cm -
3' ^) ■ 1.70 (ah, t, J=5.9H2), 4 71 f2H
J=5.9Hz) 7 nft n- ' ' ' ■ ' ^ (2H,
/-^^ ^4rf, m), 7.52-7.68 (2H, m)
Pren^r^^j^n
A mixture of ethyl ^-acetylbenzoate .
dl^nethylformamide dimethyl acetal T^ Un "
18 hours at 85°c After . 1 ''^^'^^
collected by f.i;ra ^ ^^^^^'^^^
give .ethyl , ^..sopropyl ether to
ao.44 g)!^ ^^"^^^y^^^--°P-openoyl]benzoate
(KBr) : 17I8, 1637, 1578, 1541, 1425 en"!
NMR (BMSO-d„ 5) : 2.94 (3H, 3), 3.17 ;3r3.^
^-^ -i2.2H.,;'7.;;
J=12.2Hz), 7.90-8.05 (^H, r
APCI-MASS (m/2) : 234 (M+H^)
Pr eparation ] a
To a suspension of lithium aluminum hydride ■
- tetrahydrofuran (120 ml) was added drools! a ""'^
Of --tho.ycarbonyl-4-(py_l-l-vl).y.::L: 03
anat.e , : T ^^^^ ^"""^ """^^^
(Hil mg) and the mixture was stirred at
temperature for 30 mirutes Th. ■ . ■
nix..jces. ihe insoluble mat^=.>--i ^ i o
removed bv f-in-r-^t-,- , materials were
ea oy nitration and washed with te*-rah vo^^--
fxltrate was evaporated in vacuo and t^e .esL"
purified b.v column chromatography on silica "e ,
IPVrrol-I-yi,p,,i,,„.,.^,,^^^^^J^ to ,.ve M-
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IR (K3r) : 3190, 2955, 2845, 1595, 1575, 1500 cm"^
NMR (DMSO-dg, 6) : 4.58 (2H, d, J=5.8Hz), 5.48 (IH,
t, J=5.8Hz), 6.35-6.4 (2K, n) , 7.52 (IK, dd,
J=5.6, 2.4Hz), 6.55-6.6 (2K, m) , 7.62 (IH, d,
5 J=1.9H2), 8.47 (IH, d, J=5.6H2)
.A.PCI-MASS (m/2) : 175 (M+H"^)
Preparation 19
The following compounds were obtained according to a
10 similar manner to that of Preparation 18.
(1) 3- (Pyrazol-3-yl) benzyl alcohol
IR (Film) : 3245, 2930, 2880 cra~^
NMR (DMSO-dg, 5) : 4.52 (2K, d, J=5.6Hz), 5.29 (IH,
15 t, J=5.6Hz), 6.68 (IH, d, J=2.2Hz), 7.2-7.7 (4H,
m) , 7.76 (IH, d, J=2.2Hz), 12.9 (IH, br s)
APCI-MASS (m/z) : 175 (M+H+)
(2) { 6-Phenylpyridin-3-yl ) methanol
20 IR (Film) : 3325, 2865, 1600, 1565, 1475 cm~-
NMR (CDCI3, 5) : 4.74 (2H, s), 7.4-7.55 (3H, m; ,
7.7-7.85 (2K, m) , 7.9-8.05 (2H, m) , 8.62 (IH, d,
J=l . 3Hz )
APCI-MASS (m/z) : 186 (M+H+)
25
(3) 4- ( Benzoylamino ) benzyl alcohol
IR (KBr) : 3320, 2840, 1655, 1595, 1545 cm~^
MMR (DMSO-dg, 5) : 4.50 (2H, d, J=5.7Hz), 5.22 (IH,
t, J=5.7Hz), 7.05 (IH, d, J=-7.6Hz), 7.29 (IH, d,
30 J=7.6Hz), 7.5-7.7 (4H, m) , 7.77 (IH, s), 7.96
(2H, dd, J=7.6, 1.5Hz), 10.23 (IH, s)
APCI-MASS (m/z) : 228 (M+H" )
(4) 4- ( Phenylsul fonylamino ) benzyl alcohol
35 IR (Film) : 3515, 3265, 3060, 2935, 2875, 1705,
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15
2C
35
- 39 -
1650, 1615, 1515 cin-l
NMR (DMSO-dfT, 5) ■ -4 36 fPR h t - o
6' ' ■ '■■^^ (2h, d, J=o.8Hz), 5.07 (i
J=5.8Hz), 7.02 (2H, d, J=8.6Hz), 7.15 i2R
a=8 6HZ), 7.5-7.65 (3H, , 7.7-7.8 (2H, /
10.21 (IH, s)
APCI-MASS (m/z) : 264 (M+H^)
(5) (6-Phenylthiopyridin-3-yl)niet.hanol
IR (Film) : 3320, 2865, 1590, 1560 cn-^
(CDCI3, 5) : 2.46 and 2.71 (total IH, t
J=5.6HZ), 4.64 and 4.72 (total 2H, d, J=5.6Hz)
6.88 and 7.31 (total IH, d, J=8.3Hz), 7 4-7 75
(6H, m), 8.3-8.4 (IK, m)
APCI-MASS (m/z) : 2I8 (M+K^)
(6) 4-(0xazol-5-yl)ben2yl alcohol
IR (KBD : 3330 (br) , 1510, 1491, 1041, 818 cm"!
NMR (CDCI3, 5) : 4.7, (2K, s), 7.34 (IH s)
7-35-^.50 (2H, 7.59-7.72 (2H, n) , 7.'91 (IP
s )
APCI-MASS (m/z) : 17 6 (M+H+i
(7) (3-Phenylpyrazol-5-yl) methanol
'^""^ ^^°°-3500 (br), 1471, 1360, 1030, 1001,
7 6 6 cm I
NMR (DMSO-d„ 6) : 4.38-4.58 (2H, m) , 4.95-5 37
(IH, m), 6.52-6.66 (IH, m] , 7.20-7.53 (3H n)
7.68-7.90 (2K, m) , 12.68-13.10 (^f, m)
APCI-MASS (m/z) : 175 (m+h+)
30
(8) 4- (Pyrazol-3-yl) benzyl alcohol
IR (KBr) : 2500-3600 (br) 159? i . r- -
(i-ij-;, 1 -3 5 c , 1419 T037
841, 762 cm--
NMR (DMSO-dg, 5) : 4. 51 (2H, d, J=5.7Hz), 5 07-5 - -
(IH, m), 6.60-6.74 (IH, br s) , 7.20-7.85 (5H,""m),
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12.82, 13.24 (total IH, each br s)
APCI-MASS (m/z) : 175 (M+H"^)
(9) 4- ( l-Methylpyrazol-5-yl ) benzyl alcohol
5 IR (KBr) : 2500-3600 (br) , 1495, 1460, 1425, 1385,
1273 cm"l
NMR (CDCI3, 5) : 2.12 (IH, t, J=5.7Hz), 3.88 (3H,
s), 4.77 (2H, d, J=5.7Hz), 6.30 (IH, d, J=1.9Hz),
7.35-7.52 (4H, m) , 7.51 (IH, d, J=1.9Hz)
10 APCI-MASS (m/z) : 189 (M+H"^ )
(10) 3- ( lH-Tetrazol-5-yl) benzoyl alcohol
IR (KBr) : 2100-3600 (br) , 1562, 1485, 1419,
1219 cm~-
NMR (DMSO-dg, 6) : 4.61 (2K, s), 5.20-5.60 (IH,
br), 7.48-7.65 (2H, m) , 7.85-7.98 (IH, m) , 8.05
(IH, s)
APCI-MASS (m/z) : 177 (M-rH"^)
Preoararinn 70
To a solution of 3- [ (E ) -3-dimethylaminopropenoyl ] -
benzonitrile (48.5 g) in merhanol (500 ml) was added acetic
acid (21.82 g) followed by slow additio.n of hydrazine
monohydrate (18.17 g) at room temperature and the mixture
was stirred at 17.5 hours at the same temperature. The
mixture was evaporated zo dryness and the residue was
extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was crystallized and the
crystal was collected by filtration, washed with
diisopropyl ether and dried to give 3- (pyrazol-3-
yl ) benzonitrile (37.71 g) .
IR (KBr) : 3190, 3075, 2840, 2760, 2230, 1560 cm~^
NMR (DMSO-dg, 5) : 6.88 (IH, d, J=2.1Hz), 7.62 (IH,
dd, J=7.7, 7.7Hz), 7.75 (IH, d, J=7.7Hz), 7.83
20
25
30
35
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(IH, br s), 8.16 (IH, d, J=7.7Hz), 8.24 (1H, s)
13.08 (IH, br)
5 To a suspension of sodium hydride (2.0 g) m n N-
d^znethylformamide (100 ml) was added thiophenol (5 51 g)
and the mixture was stirred at room temoerature fo>- 15 '
mxnutes. To the mixture was added 4-f luorobenzonit^xle
and the mixture was stirred at 130»C for 16 hour
-^-°gen. The mixture was poured .nto a mixture of
ethyl acetate and ice water and the separated organxc laye
was washed with water and brine, drxed over maanesium
sulfate and evaporated in vacuo. The residue was pur.fxed
by column chromatography on silica gel to give
15 4- (phenyl thio)ben2onitrile (12.24 g) as an oil
IR (Film) : 3070, 2235, 1595, 1505 cm-'-"
NMR (CDCl-3, 5) • 7 1 R--7 ■? /oil
3/ . /.15-7.3 (2H, m) , 7.65-7.8 (2H,
m) , 7.4-7.6 (5H, m)
APCI-MASS (m/2) : 212 (M-H+)
0
Prepara^jori
To a suspension of 4- (phenylsulf amoyl ) benzo^- c a-id
1.2-dxchloroetha.ne (130 ml) were added th.onyl
_ chiorxde (11.52 g) and N, N-dimethyl f ormamide (2 drops) and
the mxxture was stirred at lOO-C for 2 hours, unde^
nxtrogen. The resulting solution was evaporated xn vacuo
and the residue was dissolved xn dichloromethane (150 ml)
TO thxs solution was added N, O-dimethylhydrox vlamine-hvd^o-
chlorxde (5.19 g) , followed by dropwise addition o^
triethylamine (9.80 g) at 5°C. The mxxture was starred
room temperature for 4 hours. Water was added thereto and
the separated organic layer was washed with br-:ne a>'xed
over magnesium sulfate and evaported in vacuo. T^e .-esxdue
was purified by column chromatography on silica gel to gxve
N-methyl-N-methoxy-4-(phenylsulfamoyl)benzamide (H 31 g)
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as an oil .
IR (KEr) : 3150, 2950, 2905, 2890, 1625, 1600,
1570, 1495 cm"-
NMR (DMSO-dg, 5) : 3.24 (3H, s), 3.48 {3H, s), 7.0-
^ 5 7.2 (3H, m) , 7.2-7.3 (2H, m) , 7.7-7.9 {4H, m) ,
10.38 (IH, s)
Preparation 23
To the solution of 4-f luorobenzonitrile (10 g) and
10 pyrazole (6.74 g) in N, N-dimethylf ormamide (100 ml) was
added potassium carbonate (13.7 g) . Then the mixture was
heated for 4 hours at 120°C. After cooling, the reaction
mixture was diluted with ethyl acetate (1 f) , washed with
water, brine, dried over magnesium sulfate and evaporated
15 in vacuo. The residue was chromatographed on silica gel
(400 g, eluting with n-hexane - ethyl acetate (3:1)) to
give 4- (pyrazol-l-yl ) benzonitrile (10.54 g) .
IR (KBr) : 2226, 1608, 1529, 1394 cm"^
NMR (CDCI3, 5) : 6.54 (IH, dd, J=2.5, 1.8Hz), 7.70-
20 7.90 (5H, m) , 8.00 (IH, d, J=2.5Hz)
APCI-MASS (m/z) : 170 (M-^H"^)
Preparation 24
To the solution of 4-f luorobenzonitrile (10 g) and
25 imidazole (6.74 g) in N, N-dimethyl f ormamide (200 ml) was
added potassium carbonate (13.7 g) . Then the mixture was
heated for 2 hours at 120°C. After cooling, the reaction
mixture was diluted with ethyl acetate (2 t) , washed with
water, brine, dried over magnesium sulfate and evaporated
30 in vacuo to give 4- (imidazol-l-yl ) benzonitrile (10.34 g;
IR (KBr) : 2225, 1608, 1520 cm"^
NMR (CDCI2, 0) : 7.27 (IH, s), 7.34 (IH, t,
J=1.2Hz), 7.46-7.60 (2H, m) , 7.75-7.89 (2H, m) ,
7.95 (IK, s)
35 APCI-MASS (m/z) : 170 (M+H"^)
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- 43 -
To a solution of methyl 4- ( l-methvloyra^o^' -3-
yDbenzoate (2.5 g) m dichloro.e.hane (80 .l.'.as added
dropwxse dlisobutylalun.inu:n hydride (1 . 02M toluene
solution, 25.0 .1) at -60 - -50=C. After stirrxng for 30
-nutes at the sa.e temperature, sodium fluoride (4 28 a
and te. ,.33 , _ ^^^^^ m.xtu^e
warmed to room temperature over 15 m.nu.es and stxrred for
:: fXat"^""'" ~ —-on
The fxltrate was evaporated in vacuo to giv^ .-(i-
methylpyrazol-3-yl) benzyl alcohol (I.74 g)
IR (KBr, : 2500-3650 (br) , 1508, 1462, 1431, 1360
1302 cm-1
(CDCI3, 6) : 1.50 (IH, c, .=5.7Hz), 3.95 (3H,
!^;/-'° ^' ^=^-^Hz,, 6.54 (IH, d, .=2.2HZ),
7.33-7.43 (3.H, m) , 7.74-7.84 (2H, m)
APCI-MASS (m/z) .- 189 (M4-H-^)
Preparation pa
^° ' solution Of 4-bromo-l-methylpyrazole (1 g)
ether (15 ml) was added dropwise n-butyllithxum (1.63M .n
hexane, 4.2 ml) keeping the temperature below -60"C A^.e^
starring for 30 m.nutes, a solution of tri-n-but vl tin " '
chlor.de (1.85 ml) i. ether (1.85 ml) was added ;hereto
After stxrring for one hour, the mxxture was warmed to ;oom
temperature over 30 m.nutes and stirred for one hou^
reaction mixture was diluted with ether, washed with wa^Ir
ana br.ne, draed over magnesium sulfate, and evaporated "
under reduced pressure to give l-methyl-4-tri- (n-
butyl) stannylpyrazole (2.3 g).
IR (Neat) : 2930, 1504, 1460, 1120 cirri
NMR (CDCl^, 6) ■ 0 75-1 in lOlu
3' • u. /D i./u (27ri, m) , 3. S3 {3H, s)
7.23 (IH, s), 7.42 (IH, s)
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Preparation 27
To a suspension of 5-broinc-2-furancarboxylic acid (10
g) , N, O-dime thylhydroxylamine-hydrochloride (5.1 g) and 1-
hydroxybenzotriazole (7.07 g) in dichloromethane (300 ml)
5 was added dropwise a solution of 1 - ( 3-dimethylaminopropyl ) -
3-ethylcarbodiimide (6.37 g) in dichloromethane (60 ml) at
room temperature. The resulting mixture was stirred at
room temperature for 18 hours. Water (180 ml) was added
thereto and the insoluble materials were removed by
10 filtration. The organic layer was separated and washed
with brine, dried over magnesium sulfate, evaporated in
vacuo. The residue was chromatographed on silica gel (350
g, eluting with ethyl acetate - n-hexane (1:1)) to give 5-
bromo-2- (N-methyl-N-methoxycarbamoyl ) f uran (7.60 g) .
15 IR (Neat) : 2974, 2937, 1649, 1566, 1477 cm"^
NMR (CDCI3, 5) : 3.34 (3K, s), 3.77 (3H,. s), 6.45
(IH, d, J=3.5Hz), 7.09 (IH, d, J=3.5Hz)
APCI-MASS (m/z) : 234, 236 (M+H"")
2 0 Preparation 28
To a mixture of 3-methylbiphenyl (5.0 g) and
N-bromosuccinimide (5.29 g) in tetrachloromethane (150 ml)
was added benzoyl peroxide (144 mg) and the mixture was
refluxed for 6 hours. The mixture was cooled, and the
25 insoluble materials were filtered off. The filtrate was
evaporated in vacuo and the residue was purified by colum.n
chromatography on silica gel to give crude 3-bromomethyl
biphenyl (6.59 g) as a yellow oil.
IR (Film) : 3030, 1600, 1575 cm" -
30 NMR (CDCI3, 6) : 4.56 (2H, s), 7.35-7.7 (9H, m)
Preparation 29
The following compounds were obtained according to a
similar manner to that of Preparation 28.
35
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15
- 45 -
(1) ^-Bromo.methylbenzophenone
IR (KBr) : 3050, 1650, 1605 cm"!
NMR (CDCI3, 5) : 4.54 (2H, s), 7.4-7.85 (9H,
5 (2) 4-(Pyridin-3-yl)benzyl bromide
(-SO-d,, 5) : 6.10 ,2H, 3), 7.4-S.4 ceH, ,
8.9-9.3 (2H, m)
(3) 4-(Pyridin-2-yl)ben2yl bromide
^^^^""^ ^ ^010, 2985, 1735 1585
NMR rrnr-T ;^ . ^585, 1565 cm -
NMR (CDCI3, 5) : 4.58 (2H, s), 7.2-8.1 (7K, m) ,
8-7-8.8 (IK, m)
Prpn^T-^^-j^r^ -3n
To a solution of 4-ethoxycarbonvl-2- ( 4-
chlorophenyDthiazole (2.68 g) m a mixture of
MtT'T'"" added
l.thxum borohydr.de (218 mg) at room temoerature and the
mixture was stired at 50'C for 1.5 hou^s Th. •
20 poured int-o ■ nours . The mixture was
poured xnto a mixture of ethyl acetate and ice water, ard
the separated organic layer was washed with wate^ an^
brine, dried over magnesium sulfate and evaoora.id in
vacuo .esidue crystalline solid was collected by
25 (1 43 g " l-yl..ethanol
IH (KBr) : 3270, 3080, 2920, 2865, 1595, 15.5
1505 cm-i
NHR (DMSO-a„ 6, : ,.e3 UH. d. ..S.SHz-, 5.40 (IH
° • (2h, m)
APCI-MASS (m/2) : 226 (M-H+)
35 and dih H °' -chloronicotinate ,6.86 „
and d.hydroxypn.nyl borane ,5.85 in 1 . 2-d..ethoxyethIne
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(150 ml) was added 2M sodium carbonate aqueous solution (48
ml), followed by tetrakis ( tr iphenylphosphine ) palladium ( 0 )
(2.31 g) and the mixture was refluxed for 16 hours. The
mixture was poured into a mixture of ethyl acetate and ice
5 water, and the separated organic layer was washed with
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give methyl 6-
phenylnicotinate (7.75 g) as a white crystal.
10 IR (KBr) : 3070, 3030, 2995, 2945, 2845, 1725,
1595, 1550 cm"-
NMR {CDCI3, 6) : 3.98 (3H, s), 7.4-7.6 (3H, m) ,
7.82 (IH, dd, J=8.3, 0.9Hz), 8.0-8.1 (2H, m) ,
8.35 (IH, dd, J=8.3, 2.2Hz), 9.28 (IH, dd, J=2.2,
15 0.9Hz)
20
Prepara tion 32
The following compound was obtained according to a
similar manner to that of Preparation 31.
N-Methyl-N-methoxy-4- [ 4- ( dimethylamino ) phenyl ] -
benzamide
IR (KBr) : 3255, 3000, 2815, 1605, 1540, 1505 cm"
NMR (CDCI3, O) : 3.01 (6H, s), 3.38 (3K, s), 3.60
25 (3H, s), 6.80 (2H, d, J=8.9Hz), 7.5-7.65 (4H, mi
7.74 (2H, dd, J=6.5, 1.9Hz)
APCI-MASS (m/z) : 285 (M+K"^ )
Preparat -j nn 33
30 To a suspension of 4- (pyrrol-l-yl ) benzoic acid (3.74
g) and N, O-dimechylhydroxylamine-hydrochlor ide (1.95 g) in
dichlorom.ethane (100 ml) was added dropwise a solution of
1- (3-dimethyiaminopropyl) -3-ethylcarbodiimide (2.43 g) in
dichloromethane (15 ml) at room temperature. The resulting
35 solution was stirred at the same temperature for 18 hours.
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10
30
«arer ,„o „as added to the ..xture. and the insoluble
materials were removed by filtration. The filtrate was
separated, and the organic layer was washed with b^ine
drxed over magnesium sulfate and evaporated in vacuo 'xhe
residue was purified by column chromatography on silica gel
to give <i-<PYrrol-l-yl,-«-„ethyl-N-methoxyber.zamide ,2
g) as a white crystal.
IR (KBr) : 3130, 3045, 2975, 2935, 1640, 1610,
1580, 1525 cn"i
NMR (CDCI3, 6) : 3.39 (3K, s), 3.58 (3H, s),
6.4-6.45 (2H, m), 7.15-7.2 (2H, , 7.4-7.5 (2F
m) , 7.8-7.9 (2H, m)
APCI-MA.SS (m/2) : 231 (M+K^}
TO a suspension of 3- (pyrrol-l-yl) benzoic acid (5 62
g), N,0-diinethylhydroxylamine-.hydrochloride 93 g) and 1
hvdroxybenzotriazole (4.05 g, in dichloromethane (150 xnl )
was added drop.ise a solution of 1- ( 3-d...ethyla..nopropyl) -
-0 3-etnylcarbod.in..de (3.65 g) .n dxchioromethane (30 )
room temperature. The resulting solution was s^^'.^ed a^ ^
room temperature for 20 hours. Water (loo ml) was aadeo
t-.ereto and the insoluble materials were removed by
filtration. The fil.rate was separated and the organ.,
layer was washed wxth brrne, dried over magnesium sulfate
and evaporated xn vacuo. The residue was ourified bv
colum.n chromatography on silica gel to give 3-(pv^rol-i-
yl)-N-methyl-N-methoxybenzamide (5.19 g, as a vellowoil
IR (Film) : 3130, 2935, 1645, 1610, 1585, 1500 c^"!
NMR (CDCI3, 6) : 3.39 (3H, s), 3.57 (3H, s),
6.35-6.4 (2.H, m) , 7.1-7.15 (2H, m) , 7.45-7.6 ^^H
m) , 8.7-8.75 (IH, m)
APCI-MASS (m/z) : 231 (M+H+)
25
35
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Preparation 35
The following compound was obtained according to a
similar manner to that of Preparation 34.
5 [4- (N-Methyl-N-methoxy) carbamoylphenyl ] -
dihydroxyborane
IR (KEr) : 3380, 1610, 1545, 1510 cm~ ^
NMR (DMSO-dg, 5) : 3.25 (3H, s), 3.53 (3H, s),
7.5-7.8 (4H, m)
10 APCI-MASS (m/z) : 210 (M+H"*")
Preparation 36
To a suspension of lithium aluminum hydride (348 mg)
in tetrahydrofuran (30 ml) was added dropwise a solution of
4- (pyrrol-l-yl ) -N-methyl-N-methoxybenzamide (2.11 g) in
tetrahydrofuran {40 ml) at 5°C and the mixture was stirred
at 5°C for 1.5 hours. To the mixture were added sodium
fluoride (1.54 g) and water (495 mg) , and the mixture was
stirred at room temperature for 30 minutes. The insoluble
materials were filtered off and washed with
tetrahydrofuran. The filtrate was evaporated in vacuo and
the residue was purified by column chromatography on silica
gel to give 4- (pyrrol-l-yl) benzaldehyde (1.65 g).
IR (KBr) : 3130, 2800, 2745, 1690, 1605, 1520 cm" -
NMR (CDCI3, 5) : 6.35-6.45 (2H, m) , 7.15-7.25 (2H,
m) , 7.5-7.6 {2H, m) , 7.9-8.0 (2K, m) , 9.99 (IH,
s)
APCI-MASS (m/z) : 172 (M+H"^)
30 Preparation 37
The following compounds were obtained according to a
similar man.ner to that of Preparation 36.
15
20
25
(1) 3- ( Pyrrol-l-yl ) benzaldehyde
35 IR (Film) : 3220, 1700, 1650, 1590, 1540, 1500 cm"-
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20
"^)' 7.55-7.8 (3H, m; , ' '
(IH,
s
•9-8-95 (IH, m), 10.06
APCI-MASS (m/z) : 172 (.M+.^^)
(2) 4- ^^-DimethylaminophenyDbenzaldehyde
IH (KBr) : 2895, 2810, 2725, 1695, leoo, 159^
1540 cm--
10 . ■ 6-8-6.9 (2H, m),
(2H, m), 10.01 (IH, s)
APCI-MASS (m/z) 226 (M^.H^)
(KBr) : 3260, 3055, 2860, 1695, 1595 cir"!
-MSO-d„ 5) : 7.0-7.15 .3H, , 7.2.: 3 .2H
.),_7.93 .2H, d, .= a.lHz), 8.05 .2H, d,".:e.lHz),
10-04 (IH, s), 10.48 (IH, 3)
APCI-MASS (m/2) : 262 (M+K+)
(^) 2-Bronio-5-furaldehyde
IR (KBr) : 1670, 1464, 1377, i27i cm"!
NMR (CDCI3, 5) : 6.57 (IH, d, a=3.6;z),
25 ^' J-3.6HZ1, 9.54 (IH,
"•15 ilH,
s)
35
To a suspension of 4-bromoben2aldehyde |l 83
H-flurophenylJdihydroxyborane ,l..o L^o
was added po.de.ed po.assiu™ ca.bona.! , „ " ^o'" "
V addUion o. -t.a..3,t.„p.ospMne)pau:d : 0
<573 „g, and Che mixture was ref-uxed for 24 ^ou-T .
nitrogen. The mixture was noured xnto a J
acetate and ice water and ^he °'
"^a^er, and the separared oraar - i=..
washed with water and b^-^ne drl.H layer was
^r,H ^--ne, dried over magnesium s-ifa-P
and evaporated in vacuo. The -esldn^ , s^.ra.e
me residue was purified bv
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column chromatography on silica gel to give 4-(4-
f luorophenyl ) benzaldehyde (1.67 g) as a white crystal.
IR (KBr) : 3055, 2855, 2755, 1705, 1600, 1565,
1520 cm~^
5 NMR (CDCI3, 6) : 7.1-7.25 (2K, m) , 7.55-7.7 (2H,
m) , 7.71 (2H, d, J=8.2Kz), 7.95 {2K, d, J=8.2Hz),
10.06 (IH, s)
APCI-MASS (m/z) : 201 (M+H"^)
10 Preparation 39
To a solution of 2-bromo-5- thiophenecarbaldehyde (2 g)
and dihydroxyphenylborane (1.66 g) was added 2M sodium
carbonate solution (13.6 ml) and
tetrakis (triphenylphosphine) palladium ( 0) (605 mg) . The
15 mixture was heated for 5 hours at 80°C. The reaction
mixture was poured into water, extracted with
dichloromethane . The organic layer was washed with water
and brine, dried over magnesium sulfate, evaporated in
vacuo. The residue was chromatographed on silica gel (100
20 g, eluting with n-hexane - ethyl acetate (5:1) ) to give 2-
phenyl- 5- thiophenecarbaldehyde (1.80 g) .
IR (KBr) : 1647, 1441, 1232, 754 cm"-
NMR (CDCI3, 5) : 7.33-7.50 (4H, m) , 7.60-7.80 (3K,
m) , 9.90 (IH, s)
25 APCI-MASS (m/z) : 189 (M^H"^)
Preparation 40
The following compounds were obtained according to a
similar manner to that of Preparation 39.
30
(1) 2-Phenyl-5-f uraldehyde
IR (Neat) : 1674, 1522, 1475, 1257 cm~-
NMR (CDCI3, 5) : 6.85 (IH, d, J=3.7Hz), 7.33 (IH,
d, J=3.7Hz), 7.37-7.53 (3H, m) , 7.80-7.92 (2H,
35 m) , 9. 66 (IH, s)
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APCI-MASS (m/2) : 173 (M+H+)
(2) ^-P->ienyl-2-thiophenecarbaldehvde
IR (KBr) : 1576, 1539, 1429, 1173, .60
^ ■ --^^ ^5H, m) , 7. 82-7 90 (IH
8.00-8.08 (IK, m; , 9.98 (ih d j-i
FAB-M.Z.SS : ,89 (M^H^) ' '•''^'^
f 3 ) 4- ( 4-Methylphenyl ) benzaldehyde
(KBr) : 3095, 3060, 2860, 2765, 1690, 1600,
1575, 1505 cm"l
™« (CDCI3, 5> : 2.42 ,3H, V.29 ,2K, d
^-10. «z,. 7.55 ,2H. dd. J=6,3, l.SKz,; 7.74 „H
ad .= 5 6, X.8H.,, 7 . .4 ,2H. dd, .= 6.6, LeHz),""
10. Oo (IH, s)
APCI-MASS (m/z) : 197 (M+H+ )
(4) 4- (4-Chlorophenyl) benzaldehyde
(KBr, : 3055, 2820, 2720, 1695, 1605 err.
-1
cm
NMR ,CDCl3. 6, : 7.4-7.5 ,2H. „, , 7.55-7.65 ,2„
-I. 7.7-7.8 ,2H, 7.9-8.0 ,2K, . lo.Oo'.r--
APCI-MASS (m/z) : 217 (M+H+)
(5) A- (4-Bromophenyl) benzaldehyde
IR (KBr) : 3050, 2820, 2725, 1705, 1605, "575
1555 cm-I
NMR (CDCI3, 6) : 7.45-7.55 (2H, , 7.55-7.65 (2H,
^ ^-55-8.05 (2H, m), 10.06
(IH, s)
m) , 7.65-7.7
(IK, s)
APCI-.MASS (m/z) : 263, 261 (.m+h
^° ^ solution of 4-carboxybenzaldehvde (3 GO ■
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dropwise isobutyl chlorof ormate (3.01 g) at 5°C and the
mixture was stirred at S'C for 40 minutes. To this
solution was added aniline (2.05 g) and the mixture was
stirred at room temperature for 16 hours. Water was added
5 to the mixture, and the separated organic layer was washed
with brine, dried over magnesium sulfate and evaporated in
vacuo. To the residue was added hexane: ethyl acetate (1:1
and the powder was collected by filtration to give 4-
(phenylcarbamoyl) benzaldehyde (2.24 g). The filtrate was
10 evaporated in vacuo and the residue was purified by column
chromatography on silica gel to give the second crop (1.12
g) .
IR (KBr) : 3340, 3055, 2820, 2725, 1705, 1650,
1575, 1535 cm"^
15 NMR (DMSO-dg, 5) : 7.13 (IH, t, J=7.3Hz), 7.3-7.45
(2H, m) , 7.79 (2H, d, J=7.5Hz), 8.0-8.2 (4H, m) ,
10.12 (IH, s), 10.46 (IH, s)
APCI-MASS (m/z) : 226 (M+H"^)
2 0 Preparation 42
To a solution of ethyl 4-aminobenzoate (3.30 g) in
pyridine (10 ml) was added dropwise benzoyl chloride
(3.09 g) at 5°C, and the mixture was stirred at room
temperature for 1.6 hours. The mixture was poured into a
25 mixture of ethyl acetate, ice water and 6N hydrochloric
acid (40 ml) , and the separated organic layer was washed
with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was crystallized from
hexane and ethyl acetate (5:1), and the crystal was
30 collected by filtration to give ethyl 4- (benzoylam.ino ) -
benzoate (5.14 g) .
IR (KBr) : 3300, 3050, 2980, 1720, 1650, 1530 cm"-
NMR (DMSO-dg, 5) : 1.34 (3H, r, J=7.1Kz), 4.34 (2K,
q, J=7.1Hz), 7.5-7.7 (5H, m) , 7.95-8.2 {3H, m) ,
35 8.45-8.5 (IH, m) , 10.48 (IH, s)
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APCI-MASS (m/2) : 270 (M+H+)
Prepare h jDn 4'.
san.il '"^^ compound .as obtained according to a
simxlar manner to that of Preparation ' 4 1 .
4- f2-Pyridylcarbainoyl) benzaldehyde
IR (KBr) : 3230, 3180, 3115, 3035, 2810, 27.5
1710, 1675, 1585, 1540 cm-^
NMR (DMSO-dg, 5) : 7.20 (IH, dd, J^e.S, 1 5Hz)
7-8-7.9 (IH, m), 8.03 (2H, d, J=8.4Hz), 8.20 (2"^
d^ .= e4Hz), 8.15-3.25 UH, m), 8.4-8.45 UH, mi
10.12 (Ih, s), 11.06 (IH, s)
APCI-MASS (m/2) : 227 (M+H+)
Prep;:^r^t -.T nn
TO a solution of [2- (4-chlorophenyl) thxazoi -4-
ylj methanol (1 4^ rt) s r> ^v, t
(1-4- g) m chlorororm (80 m.l ) was added
a^.ivated manganese dioxide (5.^8 g) a-H • .
20 refluxed for 1 8 hours Th. ■ V
.i.^.at. fil-.ered and the
^- .^ate was evaporated xn vacuo .o g.ve 4-formvl-2- (.-
chlorophenyl) thiazole (1.2S g) . - ^-
"^J^^^^ ■ ''''' ''''' 1595, 1575, 1500 c"!
■• ^-^^--^S (2H, m), 8.0-8.1 (2H,
rn), 8.80 (IH, s), 9.99 hh s)
APCI-MASS (m/z) : 224 (M+H^1 ' '
Prenarat- ^- /) c
TO a solution of (3-phenylpyrazoi-5-yl , ^^thano' ,1 ^0
35
g> .n acetone (130 .1, „a3 added activated manganese
d.ox.de ,6.5 „ and t.e .ixtute was refiu.ed 1.5 hours
The .i«ure was filtered and the filtrate was evaoo^ated
vacuo to give 3-phenyl-5-formylpyrazole ,1.16 g, '
IR (KBr) : 2400-3500 ,br! , 1676, 1473, 12S2,
1192 cm-l
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NMR {DMSO-dg, 6) : 7.20-7.56 (4H, m) , 7.75-7.95
(2H, m) , 9.93 (IH, s), 14.05-14.30 (IK, br)
APCI-MASS (m/z) : 17 3 (M+H"^;
5 Preparation 46
The following compounds were obtained according to
similar manners to those of Preparations 44 and 45.
(1) 3- ( Pyra2ol-3-yl ) benzaldehyde
10 IR (Film) : 3325, 2975, 2920, 2840, 2745, 1700,
1610, 1585 cm"-^
NMR (DMSO-dg, 6) : 6.84 (IH, d, J=2.0Hz), 7.6-8.25
(4H, m) , 8.36 (IH, s), 10.07 (IH, s), 13.05 (IH
br s)
15 APCI-MASS (m/z) : 173 (M+H"^)
(2) 6-Phenyl-3-f ormylpyridine
IR (KBr) : 3060, 2835, 2785, 2740, 1695, 1590,
1560 cm"-
20 NMR (CDCI3, 5) : 7.25-7.4 (4H, m) , 7.92 (IH, d,
J=8.3Hz), 8.05-8.15 (2H, m) , 8.24 (IH, dd, J=8.
2.2Hz), 9.14 (IH, dd, J=2.2, 0.7Hz), 10.14 [IH,
s)
APCI-MASS (m/z) : 184 (M+H"^)
25
( 3 ) 2-Formyl-4- ( pyrrol- 1-yl ) pyridine
IR (KBr) : 3110, 2845, 1705, 1595 cm"^
NMR (DMSO-dg, 6) : 6.35-6.4 (2H, m) , 7.75-7.8 (2H,
m) , 7.98 (IH, dd, J=5.2, 2.5Hz), 3.12 (IH, d,
30 J=2.2Hz), 8.80 (IH, d, J=5.5Hz), 10.0 (IH, s)
APCI-MASS (m/z) : 173 (M+H^ )
( 4 ) 6- Phenyl thio- 3- f ormylpyridine
IR (Film) : 3055, 2840, 2780, 1700, 1585, 1550 cm" -
35 NMR (CDCI3, 5) : 6.94 and 7.49 (total IH, d.
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- 55 -
'total
Ih, dd, j,a.4, 2.2HZ,, 8.82 and e.ev' (total IH
d, J-2.2H2), 9.98 and 10.10 (total IF 3,
APCI-MASS (n/z) : 2I6 (.M+H+)
(5) ■'-'BenzoylarainObenzalde.hyde
I« (KBr, : 3305. 3055, 2840. 2735. 1715, 1660.
1645, 1540 cm"-
NHR (DMSO-d^, 5) - 7 =; 7 -7
6' ■ 7.0-7.7 (OH, m), 7.95-8.15 (3H,
--^-0 (IH, 3), 10.02 (IH, s), 10 54 (IH s
APCI-MASS Cn/z) : 226 (M.H^ ,
( 6 ) 4 - ( Phenyl sul f onylamino ) benzaldehyde
(KBr) : 3240, 3060, 2935, 2850, 2765, 1690,
1680, 1580, 1510 cm-1
NMR (DMSO-d^, 5) • 7 7q ^
6' . 7.29 (2H, d, J=8.6Hz), 7.55-7.7
'-'^-^-^ ^-BI (IH, s), 11.01
(IH, s)
APCI-MASS (m/z) : 262 (M+H^)
H) "^-O-ThienyDbenzaldehyde
IR (KBr) : 1589, 1601, 1211, 1157 en-
NMR (CDCI3, 5) : 7.41-7 47 f2P -7 .0
o .IX (^K, m) , 7.62 (IH, t
J=2.1Hz), 7.70-7.83 (2H, m) , 7.85-7. 98 (2H ':n^
10-02 (IH, s) ' "
APCI-MASS (n/2) : 189 (M+H+)
(8) 4- (2-Thienyl) benzaldehyde
IR (KBr) : 1699, 1601, 1213, 1170 ct"!
NMR (CDCI3, 5) : 7 14 (lu hh t c .
^ '-^^ ^If^' J=5.1, 3.7Hz), 7.40
(IH, dd, J=5.1, l.iHz), 7.47 UH, dd, J=3 7
1-lHz), 7.70-7.82 (2K, rn) , 7.82-7.96 m)
10.00 (IH, s) '
APCI-MASS : 189 (M+H+)
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(9) 4- ( Pyra2ol-3-yl) benzaldehyde
IR (Near) : 2400-3700 (br), 1697, 1606, 1211, 1171,
8 37 cm~^
NMR (DMSO-dg, 5) : 6.90 (IH, d, J=2.3Hz), 7.83 ( IH,
br s), 7.85-8.12 (4H, m) , 10.00 (IH, s), 13.13
(IH, br)
APCI-MASS (m/z) : 173 (M+H~)
(10) 4- ( l-Methylpyrazol-3-yl ) benzaldehyde
IR (KBr) : 1695, 1603, 1566, 1431, 1306 cm"^
NMR (CDCI3, 5) : 3.99 (3H, s), 6.64 (IH, d,
J=2.3Hz), 7.43 (IH, d, J=2.3H2), 7.86-8.03 (4H,
m) , 10.01 (IK, s)
APCI-MASS (m/z) : 187 (M+H"^)
( 11 ) 4- ( l-Methylpyrazol-5-yl) benzaldehyde
IR (KBr) : 1695, 1608, 1568, 1390, 1215, 1184 cm"-
NMR (CDCI3, 5) : 3.95 (3H, s), 6.41 (In, d,
J=1.9Hz), 7.56 (IH, d, J=1.9H2), 7.57-7.68 (2H,
20 m) , 7.93-8.04 (2H, m) , 10.08 (IK, s)
APCI-M-ASS (m/z) : 187 (M+K"^)
(12) 3-(lH-Tetra2ol-5-yl) benzaldehyde
IR (KBr) : 2400-3500 (br), 1674, 1612, 1560, 1373,
2 5 12 07 cm~-^
NMR (DMSO-d^, 5) : 7.86 (IH, dd, J=7.7, 7.7Hz),
8.08-8.20 (IH, m) , 8.30-8.42 (IH, , 8.57 (IH,
dd, J=1.5, 1.5Hz), 10.13 (IH, s)
APCI-MASS (m/z) : 175 (M+H*)
30
Preparation 47
To a suspension of 3- (pyrazol-3-yl ) benzonitrile (37.70
g) in formic acid (300 ml) was added a suspension of Raney
Nickel (Trademark : NDT-90) in water (130 ml) and the
35 mixture was refluxed for 3.5 hours. The mixture was cooled
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35
no^ roo. temperature and Raney Nickel was removed bv
-i-tration and washed with formi. acid ,150 nl, Tne
f.ltrate was evaporated tc dryness and dichloromethane and
water were added to the residue. The mixture was
adjusted to pH ca. 3.5 .y addition o. 5N sodium hydroxide
aaueous solution. The insoluble materials were rLZ l
celite pad a.nd t.he .iltrate was separated. Th or I L "
layer was washed with brine, dried over ma.nesrum Ll ate
co.umn Chromatography on silrca gel to give 3- ,oyrazol-3-
yDoenzaldehyde (37.17 g; . 'pyrazol 3
IR <KBr) : 3190, 2975, 2840, 1690, 1605, 1585 cm'i
<-«SO-d„ 5, : 6.8. UH, d, .= 2.2H.,, 7.65 ^l.
d-^=7.6.Hz,, 8.35 ,1H, s,, 10.07 ,1H, si, 13. C6
'1.4, br s)
Prenara| -Hnn .0
,n . ''° " °* "-"uorobenzaldehyde ,2.^8 g, and .
20 oromophenol <3..6 g, rn N, N-dimethylacetamide 20 ml 1 "
added powdered potassium carbonate ,2.7, , J'
mixture was refluxed for 17 hours. The mixture was oou^ea
xnto a m,xxture of ethyl acetate and rce water, and the
separated organic layer was washed wi.h water and t-xne
ar.ed over magnesium sulfate and evaporated in vacu^
resxdue was pur.fied by colum.n chromatography on sxl.ca'ae^
.o give 4-(4-bromophenoxylbenzaldehyde (i =,i g,
« (KBr) : 3030, 2920, 2840, 2735, 1705,' 1600,
15 60 cm -
NMR (CDCI3, 5) : 6.95-7.1 (4H, , 7. 45-. 55 (2H,
m), 7.8-7.9 (2H, m), 9.94 f^H s'
APCI-MASS (m/z) : 279, 277 (m+h^) '
Pren;:)r^h-j r^p /) q
TO a solution of 4-broniobenzaldehyde (4.96 g) and
PCT/JP95/01982
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4-f luorophenol (4.48 g) in N, N-dimethylacetamide (25 ml)
was added powdered potassium carbonate (5.53 g), and the
mixture was refluxed for 6 hours under nitrogen. The
mixture was poured into a mixture of ethyl acetate and
5 water, and the separated organic layer was washed with
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give 4-(4-
f luorophenoxy) benzaldehyde (1.92 g) as an orange oil.
10 IR (Film) : 3360, 3075, 2835, 2740, 1695, 16C0,
1585, 1495 cm"-
NMR (CDCI3, 6) : 6.7-6.8 (IH, m) , 6.85-6.95 (IH,
m) , 7.0-7.2 (4H, m) , 7.8-7.9 (2H, m) , 9.92 (IK,
s)
15 APCI-MASS (m/z) : 217 (M+H"^)
Preparation 50
To a solution of 4-phenylthiobenzonitrile (12.23 g) in
toluene (200 ml) was added dropwise diisobutylaluminum
20 hydride (1.02M toluene solution) (114 ml) at -70''C over 50
minutes and the mixture was stirred ar -70°C for 30
minutes. To the mixture were added sodium, fluoride (19.45
g) and water (6.26 g) , and the mixture was warmed to room
temperature. The insoluble materials were removed by
25 filtration and washed with toluene. The filtrate was
evaporated in vacuo and the residue was dissolved in
tetrahydrofuran (50 ml) . To this solution was added 6N
hydrochloric acid (19.3 ml) and the mixture was stirred at
room temperature for 1 hour. The mixture was extracted
30 with ethyl acetate, and the organic layer was washed wirh
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give 4-
(phenylthio) benzaldehyde (9.83 g) as a yellow oil.
35 IR (Film) : 3055, 2830, 2745, 1695, 1595, 1560,
PCT/JP95/0I982
- 59 -
1505
3' "J '.lb 7. J m, , 7.35-7.6 (3H,
ra) , 7.65-7.75 (2H, .m) , 9.91 (IH, s)
APCI-MASS (m/2) : 215 (M+H+i
Prgnar-ai- j„r|
To a solution of 4- (ovr^mi -i -,o >
(pyrazo- 1 yDbenzonitrile (5.0 g!
m dichloromethane (150 ml) was added dropwise
d..sobutylalu„,inuM hydride ,1.02M toluene solution, 58 mi,
keeping the temperature below -60-c. ,.fter stirring for
one ho sodium fluoride ,9.95 g, and water ,3.2 ml, were
added .hereto. The reaction mixture was warmed to room
temperature over 30 minutes and stirred f or 1 . 5 hours
insoluble material was removed by filtration. The filtrate
dL'soTT'""'' -^--"tion in vacuo. The residue was
TZZ Z\^^ tetrahydrofuran (25 ml,. Xo he solution was
dded IN-hydrochloric acid and stirred for one hour at room
temperature. To the mixture was added 5N-sodium hydroxide
solution (10 ml,. The ob:ectxve compound was extracted
wrth dichloromethane. The organic layer was washed w.th
water and brine, dried over magnesium sulfate, evaoorated
in vacuo. T.he residue was chromatographed on si. lea ge :
<100 g, n-hexane - ethyl acetate (1:1,, to give .-(ovrazoi-
i-yl)benzaldehyde (4.36 g).
IR (KBr) : 1695, 1605, 1390, 1200 cm-l
NMR (CDCI3, 5) : 6.54 (IH, dd, J=2.5, 1.8Hz), 7 70
(IK, d, J=1.5Hz), 7.S5-8.10 f5H, m) , 10.02 (IH
s)
APCI-MASS (m/z) : 173 (M+H+)
The following compound was obtained according to a
similar manner to that of Preparation 51.
4- (Imidazol-l-yi ) benzaldehyde
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IR (KBr) : 1686, 1606, 1522, 1313 cm"^
NMR {CDCI3, 6) : 7.15-8.10 (7H, m) , 10.05 (IH, s)
APCI-MASS (m/z) : 173 (M+K'^)
5 Preparat ion 53
To a solution of methyl 5-phenyl-3-
isoxazolecarboxylate (4.73 g) in dichloromethane (150 ml)
was added dropwise diisobutylaluminum hydride ( 1 . 02M
toluene solution 45.7 ml) at -7C°C - -60°C. After stirring
10 for one hour at the same temperature, sodium fluoride (7.83
g) and water (2.52 ml) were added thereto. The mixture was
warmed to room temperature over 30 minutes and stirred for
one hour. Insoluble materials were removed by filtration.
The filtrate was evaporated in vacuo. The residue was
15 chromatographed on silica gel (85 g, n-hexane - ethyl
acetate (3:1)) to give 5-phenyl-3-i soxazolecarbaldehyde
(1.94 g) -
IR (KBr) : 3126, 1713, 1568, 1456, 1184 cm"^
NMR (CDCI3, 5) : 6.90 (IH, s), 7.35-7.68 (3H, m) ,
20 7.75-7.92 (2K, m) , 10.20 (IH, s)
Preparat ion 54
To the solution of 4-bromobenzaldehyde (462 mg) and 1-
methyl-4-tri-n-butylstannylpyrazole (1.1 g) was added
25 tetrakis (triphenylphosphine) palladium (0) (87 mg). Then the
mixture was heated for 3 hours at 140°C. After cooling,
the reaction mixture was diluted with toluene (6 ml) . An
aqueous solution (5 ml) of potassium fluoride (1.74 g) was
added to the mixture and stirred for one hour. Insoluble
30 material was removed by filtration. The filtrate was
washed wirh warer and brine, dried over magnesium sulfate,
and evaporated in vacuo. The residue was chromatographed
on silica gel (40 g, eluting with n-hexane - ethyl acetate
(1:2)) to give 4- ( l-methylpyrazol-4-yl ) benzaldehyde (427.4
35 mg) .
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30
The
- 61 -
IR (KBr) : 1693, 1605, 1169, 831 cm-1
7-73 (Ih, s), 7.85 (IK, s), 7.80-7.92 (2H
9-98 (IH, s) ' ^'
■ ^ APCI-MASS (m/z) : 187 (m+H^)
TO a solution of oxalyl chiorid. ,1.5 nl, i„
uliK=„, , , After 20 minutes, 4- (oxazol-5-
yl,benzyl alcohol ,2.5 g, m dichloro„ethane „s „1) and
d..ethyl sulfoxide ,2 .1, „a3 added d.opwise t t^ sle
te.mperature then st-i'i-r-^w ^=
15 added trieth!, ^° ^he .nixture was
rea txon fixture was warmed to room teMperature ov»r 30
minutes. A-^te-^ c-ti-ryir^.. ^
diluted """-^^^"'^ hour, the mixture was
diluted wxtn ethyl acetate, washed with water and br^ne
r.ed over .a.nesiu. sulfate, evaporated m vacuo.
: h chro.ato.raphed on silica ,el (SO „ elutm,
with n-hexane - ethyl acetate (l:i,) to give 4- (cxazol 5
vDbenzaldehyde (2.20 g) . (cxazol-S-
IR (KBr) : 1693, 1610, 1211, llii, 829 o.-l
NMR (CDCln, 5) ■ 7 54 nu ^^ ^
25 3' J . 7.54 (Ih, s), 7.75-8.05 (4H, m) ,
8.00 (IK, s), 10.03 (IH, s)
APCI-MASS (m/z) : 174 (M+H+;
Pren3r^t--i^r^
To the solution of 3- , 1„- tet razol- 5-yl , benzaldehvde
(1.0 9) m pyridine (15 ml) was added
tripH .ohloromethane n..e „ at 0-5-c. xhe mixture was
s rred for 4 nours at room temperature. The reaction
35
-r,-! v-)-,iv-^ ' ^ -i^eacrior
-xxture was poured into water and extracted with e-hv^
acetate. The organic layer was washed wi^h dil
hydrochloric acid, water, brine, dried ovel .agnesiu.
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sulfate, evaporated in vacuo to give 3- ( 1-trityl-lK-
tetrazol-5-yl) benzaldehyde (2.51 g) .
IR (KBr) : 1699, 1516, 1491, 1446, 1201 cm" ^
NMR (DMSO-dg, 5) : 7.05-7.20 and 7.38-7.53 (15H,
5 m) , 7.80 (IH, dd, J=7.7, 7.7H2), 8.05-8.14 (IH,
m) , 8.30-8.40 (IH, m) , 8.50-8.55 (IH, m) , 10.12
(IH, s)
PrppAration 57
10 The mixture of 4- f ormylbiphenyl (3.64 g) and
cycloheptylamine (2.49 g) was heated at 120°C for 6 hours
under nitrogen. The mixture was cooled to room temperature
and dissolved in ethanol (30 ml) . To the solution was
added carefully sodium borohydride (757 mg) , and the
15 mixture was stirred at room temperature for 1 hour. The
mixture was evaporated in vacuo and the residue was
extracted with dichloromethane . The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
20 chromatography on silica gel to give N-(4-
biphenylylmethyl ) cycloheptylamine (5.24 g) as a yellow oil.
IR (Film) : 3030, 2920, 2850 cm~ ^
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.5-2.7 (IH,
m), 3.72 (2H, s), 7.3-7.7 (9H, m)
25 APCI-MASS (m/z) : 280 (M+H+)
Preparation 58
The suspension of 4- [ 4- ( dimethylamino ) phenyl ] -
benzaldehyde (640 mg) and cycloheptylamine (643 mg ) m
30 toluene (3 ml) was stirred at 120°C for 5 hours under
nitrogen. The mixture was evaporated to dryness and
dissolved in ethanol (20 ml) . To this solution was added
sodium borohydride (107 mg) and the mixture was stirred az
room temperature for 1 hour. The mixture was evaporated to
35 dryness and the residue was extracted with dichloromethane.
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15
20
25
30
35
- 63 -
The organic layer was washed wxth brine, dried over
magnesxu:n sulfate and evaporated in vacuo xh / ■ .
purified bv cm nmr. u ^acuo. The residue was
lea oy column chroma tograohy on silica r.^i .
cycloheptyl ^-!4-(ciim^^>. , ■ ^^^^^a gel to give N-
5 n.g). - '^^"^^^^y^^"^-no)phenyl]benzylamine (945
(KBr) : 3275, 3025, 2920, 2850, 2805, 1610,
1535, 1505 cm~l
^-H, m), 2.65-2.B5 (IH
APCI-MASS (m/z) : 323
The mixture of 4 -phenoxybenzaldehyde (i gs a, h
benzylamine fl fii • y^e (i.98 g) and
y amine (1.61 g) was stirred at 120°C for a h
nitroae-n TK^ ■ ^ ^ - hours under
-^e oraan.c -tracted with dichloromethane
-he organic layer was washed with brine, dried over
-agnesiu™ sulfate and evaporated m vacuo. The residue
purified by column chromatography on silica gel to
benzyl-4-phenoxybenzylar.ine ,2.07 g, . '
IR (Film, : 3035, 2915, 2820, 1680, 1505 cm"!
m?. (CDCl,, 5) ■ 3 78 , '
3' O' . 3.78 (2H, s), 3.82 (2H, s), 6.9-
T-l (14H, m)
.^PCX-MASS (m/z) : 290 (M+H+)
The mixture of 4-phenoxybenzaldehvde (l 98 „,
furfurylamma ,1.61 g, was stirred at :20-c fo; , '
under nitroaen tk^ ■ ^ l lor 4 hours
n-LLxogen. The mixture was rnr^ToH +-
..ssolved in ethanol ,20 ..^ .'Tt^ - LTIT""
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added sodium borohydride (378 mg) and the mixture was
stirred at room temperature for 1 hour. The mixture was
evaporated to dryness and the residue was extracted with
dichloromethane . The organic layer was washed with brine,
5 dried over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
to give N-furfuryl-4-phenoxybenzylamine (2.51 g) .
IR (Film) : 3060, 3035, 2920, 2830, 1590, 1505 cm~^
NMR (CDCI3, 5) : 3.76 (2H, s), 3.80 (2H, s),
10 6.15-6.2 (IH, m) , 6.3-6.35 (IH, m) , 6.9-7.4 (lOH,
m)
APCI-MASS (m/z) : 280 (M+H"*")
Preparation 61
15 The following compounds were obtained according to
similar manners to those of Preparation 57, 58, 59 and 60.
( 1 ) N- (2-Biphenylylmethyl ) -cyclohept ylamine
IR (Film) : 3060, 3020, 2935, 2910, 2850, 1460 cm"-
20 NMR (CDCI3, 5) : 1.2-1.8 (12K, m) , 2.4-2.6 (IH, m) ,
3.71 (2H, s) , 7.2-7 . 5 (9H, m)
APCI-MASS (m/z) : 280 (M+H"^)
(2 ) N-Cycloheptyl-4-phenoxybenzylamine
25 IR (Film) : 3030, 2920, 2850, 1590, 1505 cm"l
NMR (CDCI3, 6) : 1.4-2.0 (12H, m) , 2.6-2.8 (IH,
n) , 3.75 (2H, s), 6.9-7.4 (9K, m)
APCI-MASS (m/z) : 296 (M+H"^)
30 (3) N-Cyclohexyl-3-phenoxybenzylamine
IR (Film) : 3035, 2925, 2850, 1585 cm"-
NMR (CDCI3, 6) : 1.3-2.0 (12H, m) , 2.6-2.8 (IK, m) ,
3.75 (2H, s), 6.8-7.4 (5H, m)
APCI-MASS (m/z) : 296 (M+H'^)
35
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Ml "-^y<=-loheptyl-[2-H-chlorophenyl,thiazol-4-
yl ] methyl amine
IR (KBr) : 2930, 2850, 1595 en,"!
NMR ,D„SO-d„ 5, : :.3-2.2 a2n. 2.6-2.B UH
7.9-8,0 (2H, m] '
APCI-MASS (m/z) : 321 |M+H*)
IR (KBr) : 3080, 2925, 2855, 1575 cm" 1
N«« <»SO-.„ 5, = 1.3-1.9 a2H, 2.6-2.75 UH
. S2 ,2H .r 3).e.82 an. 7.0. „o,,i
, 7 2 -7.45 ,3H, 7.8-7.95 ,2H, , 12.28
(IH, br)
APCI-MASS (m/2) : 270 (M+H+)
(6) ^-Cycloheptyl-4-(pyrrol-l-yl)benzylamine
IR (Film) : 2925, 2850, 1610, 1525 cm"!
NMR (CDCI3, 5J : 1 3-2 0 npv , .
7.3-7.45 (4H, m)
APCI-MASS (m/z) : 269 (m^h^)
15
25
30
35
(7) N-Cycloheptyl-3- (pyrrol-l-yi ) benzylamine
IR (Film) : 2925, 2850, 1610, 1595, ^545 1500 -1
NMR (CDCI3, 6) : 1.4-1 95 a2H xn^ ,
6.30-6.35 ,2H, , 7.10-7.15 ,2K, 7.'l5-
7-45 (4H, m)
APCI-MASS (m/z) : 269 (M+H+)
(8) ^-Cy^l°heptyl-M-(pyrrol-l-vl).yridir-2-vnr...h i
TH /"^-i , " '^y^^'^-Li. ^ y i J methylamif^e
IR ('Xlm, : 3305. 3135, 3100, 2925, 2855, 1600
1575 cm-I
NMR (DMSO-dg, 6, : 1.3-2.0 ,12H, r„, , 2 55-7 7 „,
3.82 (2H, s), 6.35-6.4 (2H, n) 6 '
m; , D.5-6.50 (2K,
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m), 6.55-6.6 (IH, m) , 6.65-6.7 (IH, d, J=2.2H2)
8.47 (iH, d, J=5.6Hz)
APCI-MASS (m/z) : 2 82 (M+.H+)
5 (9) N-Cycloheptyl (6-phenylpyridin-3-yl)methylamine
IR (Film) : 3030, 2910, 2850, 1560 cm~^
NMR (CDCI3, 5) : 1.4-2.0 (12K, m) , 2.6-2.8 (IH, m) ,
3.83 (2H, s), 7.3-7.5 (2H, m) , 7.65-7.8 (2H, m) ,
7.95-8.05 (2H, m) , 8.61 (IH, s)
10 APCI-MASS (m/2) : 281 (M+H+)
(10) N-Cycloheptyl-3- (pyrazol-3-yl) benzylamine
IR (Film) : 3210, 2915, 2850, 1610, 1540 cm-l
NMR (DMSO-dg 6) : 1.3-1.9 (12H, m) , 2.5-2.7 (IH,
m), 3.72 (2H, s), 6.68 (IH, d, J=2.1Hz), 7.15-7.
(5H, m)
APCI-MASS (m/z) : 27 0 (M+H+)
(11) N-Cycloheptyl-4- (4-fluorophenyl) benzylamine
20 IR (Film) : 2925, 2855, 1500 cm"!
NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 2.65-2.85 (IH,
m), 3.81 (2H, s), 7.05-7.2 (2K, mj , 7.35-7.6 (6K,
m)
APCI-MASS (m/z) : 2 98 (M+H+)
25
(12) N-Cycloheptyl-4- (4-chlorophenyl) benzylamine
IR (KBr) : 3030, 2925, 2855, 1485 cm"!
NMR (CDCI3, 5) : 1.35-2.0 (12H, m) , 2.6-2.8 (IK,
m) , 3.82 (2H, s) , 7.4-7.6 (8H, m)
30 APCI-MASS (m/z) : 314 (M+H"^ )
(13) N-Cycloheptyl-4- ( 4-bromophenyl ) benzylamine
IR (KBr) : 3035, 2925, 2855, 1480 cm"!
NMR (CDCI3, 5) : 1.3-2.0 (12H, m) , 2.6-2.8 (IH,
3.81 (2H, s), 7.35-7.65 {8H, m)
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15
25
30
- 67 -
APCI-MASS (m/z) : 360, 358 (M+H+)
(14) N-Cycloheptyl-4-(4-methylphenyl)benzylanine
IR (Film) : 3025, 2910, 2855, 1500 cm-1
NMR (CDCI3, 5) : 1.3-2.0 (12H, m) , 2.39 (3H, s)
2^65-2.8 (IH, m), 3.81 (2H, s), 7.24 {2K, d'
J-7-6HZ), 7.37 (2H, d, J^8.3Hz), 7.4-7.6 {4H m
APCI-MASS (m/z) : 2 94 (M+H+)
(15) N-Cycloheptyl-4-(4-bromophenoxy)benzylainine
IR (Film) : 3030, 2925, 2850, 1585, 1505, 1480 cm"!
NMR (CDCI3, 5) : 1.3-2.0 (12H, m) , 2.6-2.8 (IH, m) ,
3.75 (2H, s), 6.8-7.0 {4H, m) , 7.25-7.5 (^H, m)
APCI-MASS (m/z) : 376, 374 (M+H+)
(16) N-Cycloheptyl-4-(4-phenylthio)benzylamine
IR (Film) : 2920, 2850, 1510 cm'^
NMR (CDCI3, 5) : 1.3-2.0 (12H, m) , 2.55-2.75 (IH,
m) , 3.75 (2H, s), 7.2-7.5 (9H, m)
^° APCI-MASS im/z) : 312 (M+H^)
(17) N-Cycloheptyl- ( 6-phenyl thxopyradxn-3-yl ) methvla^me
IR (Film) : 3305, 2925, 2850, 1700, 1585, 1560 cm-
NMR (CDCI3, S) : 1.3-2.0 (12K, m) , 2.55-2.75 (IH,
m), 3.71 (2H, s), 6.87 (IH, d, J=8.2Hz), 7.4-7.
(6H, m) , 8.35-8.4 (IH, m)
APCI-MASS (m/z) : 313 (M+H+)
35
(18) N-Cycloheptyl-4-(4-ben2oylamino)ben2ylamine
IR (Film) : 3265, 3150, 3070, 2925, 2850, 1645,
1615, 1595, 1555 cm"!
NMR (DMSO-dg, 6) : 1.3-1.9 (12H, m) , 2.55-2.7 (1k,
m), 3.69 (2H, s), 7.07 (IH, d, J=7.7Hz), 7 77'
(IH, t, J=7.7Hz), 7.5-7.8 (5H, m) , 7.9-8.o'(2H
m) , 10.22 (IH, s)
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APCI-MASS (m/z) : 323 (M+H+)
(19) N-Cycloheptyl-4- ( 2 -pyr idyl carbamoyl ) benzyl amine
IR (KBr) : 3305, 2925, 2855, 1680, 1610, 1580,
5 1535, 1505 cm"^
NMR (DMSO-dg, 6) : 1.3-1.9 {12H, m) , 2.5-2.7 (IH,
m) , 3.76 {2H, s), 7.17 (IH, dd, J=6.3, 4.9Hz),
7.45 {2H, d, J=8.2Hz), 7.98 (2H, d, J=8.2Hz),
7.8-7.9 (IH, m) , 8.19 (IH, d, J=B.4Hz),
10 8.35-8.4 (IH, m) , 10.70 (IH, s)
APCI-MASS (m/z) : 324 (M+H+ )
(20) N-Cycloheptyl-4- ( 4-f luorophenoxy ) benzylamine
IR (Film) : 2925, 2855, 1505 cm"^
15 NMR (CDCI3, 6) : 1.4-2.0 (12H, m) , 2.65-2.8 (IH, m) ,
3.75 (2H, s), 6.85-7.1 (6H, m) , 7.2-7.35 (2H, m)
APCI-MASS (m/z) : 314 (M+H"^ )
(21 ) N-Cycloheptyl-4- ( phenyl sulfamoyl ) benzylamine
20 NMR (DMSO-dg, 6) : 1.2-1.8 (12H, m) , 2.5-2.6 (IH,
m) , 3.70 (2H, s), 7.0-7.15 {3H, m) , 7.15-7.25
(2H, m) , 7.47 (2H, d, J=8.3Hz), 7.68 (2H, d,
J=8-3Hz) , 10.23 (IH, s)
APCI-MASS (m/z) : 359 (M+H+ )
25
(22) N-Cycloheptyl-4- (3-thienyl) benzylamine
IR (KBr) : 2924, 1458, 1201, 775 cm"l
NMR (CDCI3, 5) : 1.30-1.98 (12H, m) , 2.62-2.78 (IK,
m) , 3.80 (2H, s), 7.30-7.47 (5H, m) , 7.50-7.60
30 (2H, m)
APCI-MASS (m/z) : 286 (M+H"^)
(23) N-Cycloheptyl-4- ( 2-thienyl ) benzylamine
IR (Neat) : 2924, 1502, 1458, 1101, 810 cm"-
NMR (CDCI3, 6) : 1.30-1.98 (12H, m) , 2.62-2.78 (IH,
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7.22-7.40 MH, m) , 7.50-7.65 (^h m)
APCI-MASS (m/z) : 286 (M+H*)
5 (2., N-Cycloheptyl-4-,py...ol-l-yl,benzyla.,ne
IR (Neat) : 2927, 1610, 1525, 1460, 1394 cm"!
-COCl 5, : 1 .30-1.95 ,12„, . ..^.Z,,
3.81 ,2H, s,, 6.46 ,1H, t, .=2,lHz), 7 36-
J-1.6H2), 7.91 ,1H, d, J-2.1H2)
APCI-MASS (m/z) : 270 (M+H+)
(25, N-Cycloheptyl-4- ( imidazol -1-yl , b,n,yl,„,„^
IR (Neat) : 2922, 1522, 1303, 1057 cm"!
'^f"- ^' = ^-^-^-^e n2H. .,,"2.60-2.eo ,1„
- - 3 83 3,, ^_ ^^^^^^^^^ ^^^^
(iH, d, J-I.OHZ), 7.30-7.50 (4H, m) , 7 84 ,1H
APCI-MASS (m/z) : 270 (M+H^ '
20
30
.2.) --^=^°;'eptyl-4- a-»ethylpy.azol-4-yl).enzyla.lne
IR (KBr, : 3277, 2924, 1572, 1443, 1194, 802
■ ^-30-2.20 (I2H, 2.62-2.80 (IH
3.78 (2H, s), 3.94 (3H, s), 7.27-7 47 (4h"
^-^S (IH, s), 7.74 (IH, s)
APCI-MASS (m/2) : 284 (M+H+)
(27) -CycIoheptyI-2- (2-phenyItMop.e.n-5-,l ) .e..y,a..ne
IR (Neat) : 2924, 1599, 1462, 754 cn^-l
(CDCI3, 5) : 1.30-1.98 a2H, 2.^6-2 85 (1.
3.98 (2H, s), 6.87 (IH, d, J=3.6H.) 7 15""
(IH, d, J=3.6Hz), 7.18-7.45 (3H, .^) , 7.5:>-7 6^
(2H, m) - -D.
APCI-MASS (m/z) : 286 (M+H+)
35
(28) N-Cycloheptyl-4- (oxazol-5-yl , benzylamin.
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IR (KBr) : 2924, 1510, 1485, 1103, 822 cm~^
NMR {CDCI3, 5) : 1.30-1.98 (12H, m) , 2.60-2.80 (IH,
m) , 3.81 (2H, s), 7.33 (IH, s), 7.33-7.46 (2H,
m) , 7.55-7.69 (2H, m) , 7.90 (IH, s)
5 APCI-MASS (m/z) : 271 (M+H"*")
(29) N-Cycloheptyl- {2-phenylfuran-5-yl) methylamine
IR (Neat) : 2924, 1545, 1456, 1020, 760 cm~^
NMR (CDCI3, 6) : 1.30-1.95 (12H, m) , 2.64-2.80 (IH,
10 m) , 3.84 (2H, s), 6.24 (IH, d, J=3.3Hz), 6.57
(IH, d, J=3.3Hz), 7.17-7.45 (3H, m) , 7.58-7.72
(2H, m)
APCI-MASS (m/z) : 270 (M+H"^)
15 (30) N-Cycloheptyl- ( 5-phenylisoxazol-3-yl ) methylamine
IR (Neat) : 2926, 2854, 1616, 1574, 1456, 1113,
7 66 cm"-'-
NMR (CDCI3, 5) : 1.30-1.98 (12H, m) , 2.65-2.82 (IH,
m) , 3.90 (2H, s), 6.53 (IH, s), 7.34-7.53 (3K,
20 m) , 7.70-7.86 (2H, m)
APCI-MASS (m/z) : 271 (M+H"^ )
(31) N-Cycloheptyl- ( 3-phenylpyrazol-5-yl ) methylamine
IR (Neat) : 2300-3600 (br), 1570, 1460, 1358,
2 5 102 6 cm"^
NMR (CDCI3, 5) : 1.30-1.98 (12H, m) , 2.65-2.82 (IH,
m) , 3.92 (2H, s), 6.46 (IH, s), 7.20-7.50 (3H,
m) , 7 . 64-7 . 80 (2H, m)
APCI-MASS (m/z) : 270 (M+H+)
30
( 32 ) N-Cycloheptyl- ( 4-phenylthiophen-2-yl ) methylamine
IR (Neat) : 2924, 2852, 1502, 1458, 1367, 841,
735 cm"^
NMR (CDCI3, 5) : 1.32-1.98 (12H, m) , 2.70-2.88 (IH,
35 m) , 4.01 (2H, s), 7.19-7.62 (7H, m)
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15
- 71 -
APCI-MASS (m/z) : 286 (M^h^)
(33) -Cycloheptyl-.-^p,,,.,,.3__,,,,^^^^^^^^^^
(Neat) : 2300-3600 (...) , ,51., ,,56, 1350,
1205 cm-1
<1H 3.73 ,2H, SK 6.57 UH, d, j.i.s,h,,
^•30-7.90 ,5.H, 12. 70-13. .0 (IH, br,
APCI-MASS (H,/z) : 270
^----P^v.-.-a-..t..ip,„..i-3-,,,,,„,^,^^_
<KBr, .. 2922. 2852. 1510, 1«2. 1.29. 1358,
1234 cm-l
'CDCI3. : ,.30-1.93 ,12H. 2.61-2 78 ,1H
J=2.2H2), 7.29-7.40 ,3H, m) , 7.70-7 80 ,2H 'm,
APCI-MftSS ,m/z, : 284 ' '
.35, «-y=i°'>eptyl-4-,l-.ethyl.ny«zol-5-.vl,ben.yl..i.e
IH (Neat, : 2924. 2854. 1493. 1462. 1385 1273 1-1
3 i-J^ 1.98 (12H, m), 2.62-2.81 (IK
-I.9HZ), V.33-V.,6 (,„, ,.3, ,,,, ,
J=1.9Hz)
APCI-MASS (m/z) : 284 (M+H+)
(36) ^^-Cycloheptyl-3-(l-trityl-lH-tetrazoI s i..
2852, 1697, 1515, 1452, 750
698 cm-1
^' ^ — 2.62-2.78 aH
; : ^-^ ° .-H. 7.96-8.1;
(2H, m)
FAB-MASS (m/z) : 514 (M+H+)
35 (37) N-CycloheptyI-4-(phenylcarba.oyl).enzyla..ne
20
25
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IR (KBr) : 3475, 3345, 3055, 2925, 2850, 1645,
1600, 1525, 1505 cm" ^
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.5-2.65 (IH,
m), 3.78 (2H, s), 7.09 {IH, t, J=7.3Hz), 7.35
5 (2H, S), 7.48 (2H, d, J=8.2K2), 7.78 (2H, d,
J=7.5H2), 7.90 (2H, d, J=8.2Hz), 10.20 (IH, s)
APCI-MASS (m/z) : 323 (M+H^ )
( 38 ) N-Cycloheptyl-4- (phenylsulf onylamino) benzylamine
10 IR (KBr) : 3130, 3015, 2930, 2855, 1610, 1570,
1505 cm~^
NMR .(DMSO-dg, 5) : 1.2-1.8 (12H, m) , 2.5-2.6 (IH,
m) , 3.58 (2H, s) , 6.99 (2H, d, J=8.5Hz), 7.16
(2H, d, J=8.5Hz), 7.45-7.6 (3H, m) , 7.65-7.75
15 (2H, m)
APCI-MASS (m/z) : 359 (M+H+)
Pr«=-para t ion 62
The mixture of 4- f ormyl-2- ( 4-chlorophenyl) thiazole
20 (2.24 g) arid benzylamine (2.14 g) was stirred at 120°C
under nitrogen for 5 hours. The mixture was cooled to room
temperature and dissolved in ethanol (30 ml) . To this
solution was added sodium borohydride (378 mg) and the
mixture was stirred at room temperature for 1.1 hours. The
25 mixture was evaporated to dryness and the residue was
extracted with dichloromethane . The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography to give N-benzyl- [ 2- ( 4-chlorophenyl) thiazol-
30 4-yl] methylamine (3.22 g) .
IR (Film) : 3060, 3030, 2915, 2835, 1495 cm~^
NMR (DMSO-dg, 5) : 2.64 (IH, br s), 3.67 {2H, s),
3.78 (2H, s), 7.2-7.4 (5H, m) , 7.52 (IH, s), 7.5-
7.6 (2K, m) , 7.9-8.0 (2H, m)
35 APCI-MASS (m/z) : 315 (M+H+)
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25
30
- 73 -
The mixture of 3-bromomethylbiphenyl (6.58 g) and
cycloheptylamine (6.03 g) was stirred at 120°C for 3.5
hours under nitrogen. The mixture was cooled to room
temperature, and the mixture of dichloromethane and wate^
were added thereto. The separated organic layer was washed
with brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography
on silica gel to give N- (3-biphenylylmethyl ) -
cycloheptylamine (4.49 g) as an orange oil.
IR (Film) : 3060, 3030, 2920, 2850, 1460 cm"!
NMR (CDCI3, 6) : 1.4-2.0 (12H, m) , 2.7-2.85 (IH,
m), 3.85 {2H, s), 7.3-7.7 {9H, m)
APCI-MASS (m/2) : 280 (M+H+)
Prepa r ation 64
The following compounds were obtained according to
similar manners to those of Preparations 62 and 63.
20 (1
N-Cycloheptyl-4- (pyridin-3-yl ) benzylamine
NMR (CDCI3, 6) : 1.3-1.9 (12K, m) , 2.9-3.05 (IH,
m), 7.3-7.6 (5H, m) , 7.8-7.9 (IH, m) , 8.5-8.6
(IH, m) , 8.8-8.85 (IH, m)
APCI-MASS (m/2) : 281 (M+H+)
(2) N-Cycloheptyl-4- (pyridin-2-yl ) benzylam.ine
IR (Film) : 3050, 3005, 2920, 2850, 1585, 1565 cm"-
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.6-2.7 (IH,
m), 3.74 {2H, s), 7.25-7.5 (3H, m) , 7.8-8.1 '(4H,
m) , 8.6-8.7 (IH, m)
APCI-MASS (m/z) : 281 (M+H+)
(3) N-Cycloheptyl-4- ( 4-benzoyl ) benzylamine
IR (Film) : 3050, 2925, 2850, 1655, 1605 cm"-
35 NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 2.6-2.8 (IH, m) ,
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3.87 (2H, s), 7.4-7.65 (5H, m) , 7.75-7.9 (4H, m)
APCI-MASS (m/z) : 308 (M+H"^)
PrP^nriration 65
5 To a solution of 3- (2-inethylthiazol-4-yl ) -
benzylamine-hydrochloride (2.41 g) in a mixture of
dichloromethane (30 ml) and water (10 ml) was added 5N
sodium hydroxide aqueous solution and adjusted to pH 9-10.
The separated organic layer was washed with brine, dried
10 over magnesium sulfate and evaporated in vacuo. To the
residual oil was added cyclohepranone (1.68 g) and the
mixture was stirred at 120°C under nitrogen. The mixture
was cooled to room temperature and dissolved in ethanol (30
ml ) . To this solution was added sodium borohydride (378
15 mg) and the mixture was stirred at room temperature for 2.5
hours. The mixture was evaporated to dryness and the
residue was extracted with dichloromethane. The organic
layer was washed with brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purified by
20 column chromatogaphy on silica gel to give N-cycloheptyl-3-
( 2-m.ethylthiazol-4-yl ) benzylamine (2.07 g) as a yellow oil.
IR (Film) : 3380, 2915, 2855, 1455 cm"^
NMR (CDCI3, 6) : 1.30-2.0 (12H, m) , 2.7-2.85 (IH,
m) , 2.76 (3H, s), 3.82 (2H, s), 7.32 (IK, s),
25 7.25-7.4 (2H, m) , 7.75-7.9 (2H, m)
APCI-MASS (m/z) : 301 (M+H"^)
Preparation 66
To a suspension of N-cyclohepty 1- 4 - ( 4 -
30 benzoyl ) benzylamine (1.87 g) in ethylene glycol (10 ml)
were added potassium hydroxide (511 mg) and hydrazine
monohydrate (1.95 g) , and the mixture was stirred at 150°C
for 5 hours and at 200°C for 4 hours. The mixture was
poured into a mixture of dichloromethane and ice water, and
35 the separated organic layer was washed with water and
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brine, dried over magnesium sulfate and evaporated in
vacuo The resxdue was purified by column chro.atograohv
on s.l.ca gel to give N-cycloheptyl-4- ( 4-benzyl ) .enzylamine
li.^y g) as an orange oil.
5 IR (Film) : 3025, 2905, 2850, 1510 cir-i
NMH (CDCI3, 5) : 1.4-2.0 (12H, m) , 2.6-2.8 (IH, m) ,
3.74 (2H, s), 3.96 (2H, s), 7.1-7.4 (9H, rn)
APCI-MASS (m/z) : 294 (M+H+)
Pren;:^r^h inn «=^7
To a solution of 3- (pyrazol-3-yl , benzaldehyde (4 33 a)
xn pyridine (20 ml) was added trityl chloride (7 71 g)"
under ice cooling. The mixture was stirred for 30 m.nutes,
and then warmed to room temperature. After stirring for 3
hours at the same temperature, the reaction mixture was
poured into ice aqueous hydrochloric acid, extracted with
ethy. acetate. The organic layer was washed with wate. and
brxne, dried over magnesium sulfate, and evaporated in'
vacuo. The residue was purif.ed by column chromatography
on silica gel (elutxng with n-hexane - ethyl acetate (2-1))
to give 3-(l-tritylpyrazol-3-yl)benzaldehyde (9 26 g)
IR (KBr) : 3477, 3060, 3030, 1697, I6OI, 1491,
14 4 4 cm~^
NHR (DMSO-dg, 5) : 6.93 (IH, d, J=2.5Hz), 7. .-7 5
(16H, m), 7.63 (IH, dd, J=7.7, 7.7Hz), 7.85 (IK
J-7.7HZ), 8.08 (IH, d, J=7.7Hz), 8.25 (IH si
10.04 (IH, s)
Preparation f.R
T.he mixture of 3- ( l-tritylpyrazol-3-yl ) benzaldehvde
(15.31 g) and benzylamine (7.91 g) was stirred at i:^0°c fo-
o hours under nitrogen. The mixture was cooled to ^oom
temperature and dissolved in ethanol (120 ml) To ^h^ s
solution was added carefully sodium borohydride (1 40 g) a-
room temperature and the mixture was stirred for . hours
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The mixture was concentrated in vacuo and to the residue
were added dichloromethane and ice water. The separated
organic layer was washed with brine, dried over magnesium
sulfate and evaporated in vacuo. The residue was purified
5 by column chromatography on silica gel to give N-benzyl-3-
( l-tritylpyrazol-3-yl ) benzylamine (12.18 g) as an amorphous
solid.
IR {KBr) : 3059, 3028, 1599, 1493 cm~^
NMR (DMSO-dg, 5) : 3.65-3.75 (4H, m) , 6.77 (IH, d,
10 J=2.5Hz), 7.05-7.45 (IBH, m) , 7.55-7.75 (2H, m)
Preparation 69
To a suspension of N-benzyl-3- { l-tritylpyrazol-3-
yl ) benzylamine (8.60 g) in anisole (17.2 ml) was added
15 trif luoroacetic acid (34.4 ml) at room temperature and the
mixture was stirred at BO°C for 3.5 hours. The mixture was
concentrated in vacuo and the residue was pulverized with
diisopropyl ether. The powder was collected by filtration,
washed with diisopropyl ether and dried in vacuo to give N-
20 benzyl-3- (pyrazol-3-yl ) benzylamine bis (trif luoroacetate)
(7.35 g) .
IR (KBr) : 3059, 3005, 1669, 1510, 1489 cm"^
NMR (DMSO-dg, 5) : 4.2-4.3 (4H, m) , 6.70-6.75 (IK,
m) , 7.1-7.6 (7H, m) , 7. -75-8.0 ;3K, m)
25
Prep;^ration 70
To a solution of 2 , 4-dichloro-6-methyl-3-nitropyridine
(30.33 g) in acetonitrile (100 ml) was added dropwise
sodium methoxide (28'-= methanol solution) (85.1 ml) at 5°C,
30 and the mixture was stirred at SO^C for 6 hours. The
mixture was cooled and poured into a mixture of ethyl
acetate and ice water. The separated organic layer was
washed with water and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purified by
35 column chromatography on silica gel to give 2 , 4-dimethoxy-
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6-n,ethyl-3-nitropyridine ,28.21 „ as a pale yellow
crystal.
(KBr) : 3093, 3035, 3005, 2960, 2868, 1601, 1581
1531 cm-1
' NMR (DMSO-d^, 6) : 2 44 f3H c, i ^ q-,
^ s), 3.92 and 3.94 { 6H,
s X 2), 6.97 (IH, s)
APCI-MASS (m/z) : 199 (M+H+)
To a solution of 2, 4-diinethoxv-6-inethyl-3-
UoT'rr''" r'-' ^'--^o-ne (200 .1, and methanol
(100 xul) was added 10. palladia, on carbon (14 g) under
nxtrogen and the fixture was hydrogenated under at.osoher.c
pressure for 4 . 5 hours. Palladium on carbon was filtered
Off and the filtrate was evaporated in vacuo. The residue
was pur.fred by column chromatography on sil.ca gel to give
3-amxno-2,4-dimethoxy-6-methylpyridine (23. 4^ g) as an
orange oil.
(Film) : 3458, 3373, 2945, 2856, 1605 cm"!
NMR (DMSO-d^, 6) : 2 26 f3H ^> -5 -7..
^ ' ^-^^ s) , 3.79 and 3.82 ( 6.H
s X 2), 3.96 (2H, br s), 6.52 (IH, s)
APCI-MASS (iti/2) : 169 (M+H+)
Prenarat-inp lo
TO a solution of 3-amino-2, 4-bis (methyl thio) -6-
n.ethyipy.i,ii,e (7.90 g) m dxchloro.ethane (160 ml) was
added N,N-dimethylaniline (5.73 g) at 5»C, followed by
dropwise addition of phenyl chlorof ormate (6.78 g) .^e
mixture was warmed to room temperature and stirred at '4
hours. TO the mixture were added ice water (60 ml) and 6N
hydrochloric acxd (10 ml), and the separated organic lave,
was washed with brine, dried over magnesium sulfate and' '
eva rated m vacuo. The residue was crystallized, and the
crystal was collected by filtration, washed with
diisopropyl ether and dried in vacuo to give 3-
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phenoxycarbonylamino-2, 4-bis (methylthio) -6-methylpyridine
(10.46 g) .
IR (KBr) : 3410, 3228, 3196, 3145, 3003, 2926, 1732,
1591, 1556, 1537 cm~-
NMR (DMSO-dg, 5) : 2.45 (6H, s), 2.46 (3H, s), 6.94
(IK, s), 7.0-7.5 (5H, m) , 9.48 (IH, br s)
APCI-MASS (m/z) : 321 (M+H"^)
Prpparat.ion 73
10 To a solution of 2, 4 , 6-trif luoroaniline (883 mg) and
N, N-dimethylaniline (0.91 ml) in methylene chloride (18 ml)
was added phenyl chlorof ormate (0.83 ml) and the mixture
was stirred at room temperature for 4 hours. The reaction
mixture was washed with IN-hydrochloric acid (three times) ,
15 water, aqueous sodium bicarbonate, water, and brine. The
organic layer was dried over magnesium sulfate and
evaporated in vacuo. The resulting solid was collected and
washed with n-hexane to give phenyl N- (2,4,6-
tri fluorophenyl ) carbamate (1.46 g) .
20 IR (KBr) : 3253, 1749, 1722, 1538, 1240, 1200 cm" ^
NMR (CDCI3, 5) : 6.26 (IH, br s), 6.70-6.86 (2K, m) ,
7.10-7.46 {5H, m)
APCI-MASS (m/z) : 268 (M+H"^)
2 5 Preparation 74
To a solution of 3-amino-2 , 4-dimei:hoxy-6-
m.ethylpyridine (23.40 g) in dichloromethane (200 ml) was
added N, N-dimethylanilxne (20.23 g) , followed by dropwise
addition of phenyl chlorof ormate (23.94 g) at 5°C. The
30 mixture was warmed to room temperature and stirred for 3
hours. The resulting precipitates were collected by
filtration, washed with dichloromethane and diisopropyl
ether, and dried in vacuo to give 2 , 4-dimethoxy- 6-methyl-3-
phenoxycarbonylaminopyridine (21.95 g) as a white crystal.
35 IR (KBr) : 3408, 3251, 3147, 3064, 2983, 2947, 2860,
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1713, 1593, 1497 cm-'-
NMR (DMSO-d„ 6) : 2.38 (3H, s), 3.85 (6H, s),
6.72 (IH, s), 7.05-7.3 (3H, m) , 7.35-7.45 (2K,
in), 8.83 (IH, br)
5 APCI-MASS (m/z) : 289 (m+h+)
Pren^r;:^l- ion 75
A mixture of 4- (4-bromophenoxy) benzaldehyde (10 0 g)
and benzylamine (5.42 g) was stirred at 120°C for 4 hours
10 After cooling to room temperature, the resulting solid was
suspended in ethanol (150 ml) . To the suspension was added
carefully sodium borohydride (1.36 g, , and the mixture was
stzrred at room temperature for 2 hours. The mixture was
evaporated in vacuo and the residue was extracted with
methylene chloride. The organic layer was washed with
water, brine, dried over magnesium sulfate, and evaporated
in vacuo. The residue was purified bv column
Chromatography on silica gel (250 g, elutxng wxth methvle^e
chloride - methanol (20:1)) to give N-benz vl-4- ( 4-
bromophenoxy) benzylamine (11.51 g) as a pale yellow oi^
IR (Near) : 3061, 3028, 2700-3000 (br), 1608, 1583,
1504, 1481, 1240 cm~-
NMR (CDCI3, 5) : 3.79 (2H, s), 3.82 (2H, s),
6.80-7.00 (4H, m) , 7.20-7.50 (9H, m)
25 APCI-MASS (m/2) : 368, 370 (M+H^)
Preparat ion 76
The mixture of 3- ( 1- tritylpyrazol-3-yl ) benzaldehyde
(9-18 g) and cycloheptylamine (3.75 g) was stirred at IC^O^C
for 4 hours. The mixture was cooled to room temperature^
and dissolved m ethanol (120 ml). To this solution v:^.
added sodium borohydride (836 mg) and the mixture was
stirred at room temperature for 2 hours. The mixture was
evaporated in vacuo and extracted with methylene chloride
The organic layer was washed with water and brine, dried
20
30
35
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over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
(eluting with methylene chloride - methanol (40:1 to 10:1))
to give N-cycloheptyl-3- ( l-tritylpyrazol-3-yl ) benzylamine
5 (7 . 92 g) .
NMR (DMSO-dg, 6) : 1.20-1.90 (12K, m) , 2.50-2.70 (IH,
m) , 3.69 (2H, s), 6.77 (IH, d, J=2.5Hz), 7.05-
7.50 (12H, m) , 7.55-7.65 (IH, m) , 7.71 (IH, s)
APCI-MASS (m/z) : 512 (M+H"^)
10
Preparation 77
To a suspension of 3-amino-2 , 4 , 6-
trimethylpyridine • hydrochloride (5.18 g) in 1,2-
dichloroethane (120 ml) was added diisopropylethylamine
15 (19.39 g) at room temperature, followed by addition of
phenyl chlorof ormate (7.05 g). The mixture was refluxed
for 10 hours under nitrogen. The mixture was cooled and
poured into ice water. The separated organic layer was
washed with brine, dried over magnesium sulfate and
20 evaporated in vacuo. The residue was purified by column
chromatography on silica gel co give 3-
phenoxycarbonylamino-2 , 4 , 6- trimethyl pyridine as a crude
orange oil (3.17 g) .
IR (KBr) : 3275, 2924, 1740, 1713, 1605, 1550 cm"l
25 NMR (DMSO-dg, 6) : 2.22 (3H, s), 2.39 (6H, s), 7.01
(IH, s), 7.2-7.6 (5H, m) , 9.42 (IK, brs )
-A.PCI-MASS (m/z) : 257 {M+H"^)
Preparat ion 78
30 To a suspension of 4-chloro-6-methyl-2-methylthio-3-
nitropyridine (16.0 g) in a mixture of 1,4-dioxane (200 .ml)
and methanol (50 ml) was added Raney-Nickel (NDT-90;
trademark: Kawaken fine chemicals) (ca. 30 g) under
nitrogen, and the mixture was hydrogenated under
35 atomospheric pressure for 3 hours. Raney-Nickel was
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10
15
20
25
30
35
rxltered off and the filtrate was evaporated in vacuo
reszdue was purified by column chro^atographv ' on sU^^a
to give 3-ar„ino-2-=hloro-6-.ethyl-4-..ethylth;oovridin"e
(12.86 g) as an orange oil.
IR (filn.) : 3424, 3322, 2922, 1707, 15O6, 1570
1529 cm"-
NMR (DMSO-d„ 5, : 2.29 ,3H, s,, 2.31 .-3:., 3;, . 93
(2H, brs), 6.98 (IH, s)
APCI-MASS (m/z) : 191, igg j
Prenar^ tinn 7ci
TO a solution of 3-amino-4-ch.loro-6-methyi
methylthiopyrid.ne (12.75 g) xn dichloro.ethane ^.00 .1,
was added N, N-di.ethylanil.ne (6.00 g) a. 5»c, .o^owed .y
dropwxse addxtxon of phenylchlorof orznate (7 g)
n^ixture was warmed to rooxn temperature and stirred ac^^e
same temperature for 4 hours. The mixture was washed with
ailute hydrochloric acid and brine, d^ied ove.
, a-J-ed over magnesium
sulfate and evaporated in vacuo. The residue was
rr.turated with diisopropyl ether and collected o--
titration, washed with diisopropyl ether and d^ied r
vacuo under phosphorus pentoxide to gxve 2-chloro- tr -
4-methylthio-3-phenoxycarbonylam.nopyridine (9 58 g) '
IR (KBr) : 3194, 2924, 1751, 1579, 1514, 1489 cm"!
NMR (DMSO-dg, 6) : 2.29 (3H, s), 2.50 (3P
6.7-6.85 {3H, m), 6.98 (IH, s), 7.1-7.25 j.H m,
9-35 (IH, brs) ' '
Pr eparation ro
TO a solution of 3, 5-di-tert-butyl-.-.Hydroxyohe.nol
9 65^, and imidazole ,3.55 g, in N, H-di.ethyl f or.ara.de
(80 .^.1, was added tert-butyldimethylsilyl c.hlo-ide ,-6 =.4 o-
at 5-c, and the .fixture was stirred at roo. temoeratu^V ^o'^
3 hours. The mixture was poured .nto a .fixture of ethv" "
acetate and ice water, and the se.oarated orga.n.c iaver'^as
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- 82 -
washed with water and brine, dried over rr.agnesi^am sulfate
and evaporated in vacuo. The residue was purified by
column chromacography on silica gel to give 1-tert-
butyldiniethylsilyloxy-3, 5-di-tert-butyl-4-hydroxybenzene
(13.91 g) as a white solid.
IR (KBr) : 3651, 2958, 2929, 2858, 1601, 1470 cm"-
MMR (CDCI3, 5) : 0.18 (6H, s), 0.91 (9H, s),
1.41 (18H, 3) , 6.73 (2K, s)
APCI-MASS (m/z) : 336 (M"^)
PT-opar;=ir i nn 81
To a suspension of sodium hydride (60% oil dispersion)
(1.65 g) in N, N-dimethylf ormamide (100 ml) was added
dropwise a solution of l-tert-butyldimethylsilyloxy-3 , 5-di-
15 tert-butyl-4-hydroxybenzene (13.89 g) in N,N-
dimethy If ormamide (70 ml) ar 5°C, and the mixture was
stirred at the same temperature for 1 hour. To the
resulting solution was added chloromethyl methyl ether
(4.99 g) at 5°C and the mixture was stirred az room
20 remperature for 5 hours. The mixture was poured into a
mixture of ethyl acetate and ice water, and the separated
organic layer was washed with water and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give 1-
25 tert-butyldimethylsilyloxy-3, 5-di-tert-butyl-4-methoxy
m.ethoxybenzene (13.49 g) as a yellow solid.
IR (KBr) : 2962, 2929, 2897, 2860, 1597 cm"^
NMR {CDCI3, 5) : 0.19 (6H, s), 0.9S (9H, s), 1.41
(18H, s), 3.62 (3H, s), 4.36 (2H, s), 6.72 (2H,
30 s)
AFCI-MASS (m/z) : 381 (M+H"^)
Prepara l-inn 82
To a solution of l-tert-butyldimethylsilyloxy-3, 5-di-
35 tert-butyl-4-methoxymethoxybenzene (13.42 g) in
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tetrahydrofuran (20 ml) was added 1 . OM solution of
tetrabutylanunoniuxn fluoride (38.8 ml) at room' temperature
and the mixture was stirred at the same temoeratu^e for 2
hours. The mixture was poured into a mixture of ethyl
acetate and ice water and the separated organic layer was
washed With water and brine, dried over magnesia sulfate
and evaporated in vacuo. The residue was purified by
column chromatography on silica gel to give 3, 5-di-tert-
butyl-4-methoxymethoxyphenol (9.43 g) as a yellow crystal
^^^"^ •• ''''' 2958, 2910, 2870, 2779, 161o'
1589 cm-1
NMR (CDCI3, 5) : 1.42 (18H, s), 3.63 (3H, s),
4.87 (2H, s), 6.74 (2H, s)
TO a solution of 1" ( 4-f luorophenoxy) -4-nitrobenzene
(22 9 g) xn ethyl acetate (200 ml) was added 10^. palladium-
cari^on (50. wet) (9.16 g) , and the mixture was hvdrogenated
under atmospheric pressure at room temperature for 3 hours
Palladaum on carbon was filtered off and washed with
tetrahydrofuran. The filtrate was evaporated .n vacuo and
^he residue was purified by column chromatography on s.-l.ca
gel to give 4- ( 4-f luorophenoxy) aniline (18.27 g) as a red
powder .
^^^"^ '■ 3395, 3325, 3230, 3070 3045, 3020,
1635, 1490 cm"l
NMR <CDCl3. 5, : 6.65-6.75 ,2H, , 6.8-7.05 ,6H.
APCI-MASS (m/z) : 204 (M+H+)
To a solution of 3- { 4-f luorophenoxy) benzyl alcohol
(3.97 g) in chloroform (50 ml) was added activated
manganese dioxide (15.82 g) and the mixture was re^luxed
for 4.5 hours. Manganese dioxide was filtered off and the
filtrate was evaporated in vacuo to give crude 3- (4-
20
35
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f luorophenoxy) benzaldehyde (3.81 g) as a yellow oil.
IR (Film) : 3074, 2837, 2819, 2731, 1701, 1585, 1502,
14 81, 14 50 cm"l
^MR (DMSO-dg, 5) : 7.1-7.45 (6H, m) , 7.55-7.75 (2H,
5 m) , 9.98 (IH, s)
Preparati on 85
To a suspension of lithium aluminum hydride (5.69 g)
in tetrahydrofuran (300 ml) was added dropwise a solution
10 of 4- (4-f luorophenoxy) benzonitrile (21.32 g) in
tetrahydrofuran (200 ml) at 5°C, and the mixture was
stirred at room temperature for 4 hours. To the mixture
was added sodium fluoride (16.80 g) , followed by dropwise
addition of cold water (5.41 g) and the mixture was stirred
15 at room temperature for 45 minutes. The insoluble
materials were filtered off and washed with
tetrahydrofuran. The filtrate was evaporated in vacuo and
the residue was purified by column chromatography on silica
gel to give 4- ( 4-f luorophenoxy) benzylamine (21.39 g) as a
20 yellow oil.
IR (KBr) : 3352, 3269, 3043, 2864, 1645, 1606,
14 95 cm"l
NMR (DMSO-dg, 5) : 3.69 (2H, s), 6.9-7.4 (8K, m)
APCI-MASS (m/z) :201 (-M+K'^-NH3)
25
Preparation 86
To a solution of phenyl chlorof ormate (31.2 g) in 1,2-
dichloroethane (250 ml) was added dropwise a solution of
3-amino-2 , 4 , 6-trimethylpyridine (22.62 g) in 1,2-
30 dichloroethane (120 ml) at 100°C, and nhe mixture was
refluxed for 1 hour under nitrogen. The mixture was cooled
zo room temperature and added dropwise a mixture of ethyl
acetate (2 C) and tetrahydrofuran (10. The precipitates
were collected by filtration, washed with ethyl acetate and
35 diisopropyl ether and dried in vacuo over phosphorus
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20
- 35 -
pentoxide to give 2, 4 , 6-trimethyl-3-
Phenoxycarbonylaminopyridine-hydrochloride i4B 8. g)
IR (KBD : 3413, 1741, 1645, 1541, 1483 cir,-!
NMR (DMSO-de, 5) : 2.49 (3H, s,, 2.69 (6H, s)
V.2-7.5 (5H, m), 7. 65-7.75 (IH, n.) , 9.63 and
10.20 (total IH, br s)
APCI-MASS (m/z) : 257 (M+H+-HC1)
Freparatinn ff7
10 TO a solution of 5-ainino-4, 6-bis (methvlthio) -2-
.nethlpy^i,,,,,, (,.,0 g) in dichloro.etha;e (BO .1) was
added N,N-di.ethylaniline (2.96 g) at 5=C, followed by
dropw.se addition of phe.nyl chlorof or.ate (3.51 g, The
^.xture was stirred at roo. temperature for 2 hours unde.
lTrZ\ ^'""^^ ^^^^ ^^^^^^ hydrochlorxc
acxd and br.ne, dried over .agnesiu. sulfate and evaporated
xn vacuo. The residue was triturated with d.iso.ropyl
ether collected by filtration, washed with d.isopropy.
ether and dr.ed in vacuo to give 4 , 6-bis (.ethvlthxo ) -2-
methyx-5-phenoxycarbonylaminopyrimidine (5 74 g^
IH (KBr) : 3217, 3005, 2924, 1711, 1595, 1^85 c.-^
NMR (DMSO-dg, 6) : 2.49 (6H, s), 2.59 (3H, s),
7.0-7.5 (5H, m), 9.27 and 9.68 (total IH 's)
APCI-MASS im/z) : 322 (M+H+)
25
Pre'.p^T;=^tin-n ft ft
To a solution of 2- ( 3-bromophenyl , - i , 3-dioxolane
(-0.42 g) and triisopropoxyborane (25 lA g) ^
I1.70M haxana solution, 78.8 =,1, at -72-c ove- .-hours
under nitro.e.. The fixture was „arMed to roo. temperature
and starred for 21 hours. The rarxture was poured into a
mrxture of ethyl acetate and dilute hydroohlorro acid and
the separated organic layer was washed with water and
brxne, dried over magnesium sulfate and evaporated rn
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2C
25
30
- 56 -
vacuo. The residue was purified by column chromatography
on silica gel to give crude dihydroxy- ( 3- f orrnylphenyl ) -
borane (14 . S3 g) .
IR (K3r) : 3354, 2840, 1678, 1603, 1581 cm~-
NMR (DMSO-dg, 5) : 7.55-7.7 (IK, m), 7.8-8.15 (2H,
ra) , 8.33 (2H, s), 10.03 (IH, s)
Prpparatinn 89
To a suspension of 4-bromG-l-tritylpyrazole (18.96 g)
and crude dihydroxy- < 3- f orrnylphenyl ) borane (14.6 g) in
toluene (400 ml) were added powdered potassium carbonate
(10.10 g) and tetrakis ( triphenylphosphine ) palladium ( C )
(2.81 g), and the mixrure was refluxed for 6 hours. The
mixture was poured into a mixture of ethyl acerate and ice
water, and the separated organic layer was washed with
brine,, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography
on silica gel zo give 3- ( l-tritylpyrazol-4-yl ) benzaldehyde
(2.65 g) as a yellow solid.
IR (KBr) : 3057, 3024, 2812, 2727, 1699, 1603,
158 5 cm" '
MMR (DMSO-dg, 6) : 7.0-7.15 (5H, m) , 7.35-7.5 iiCH,
m) , 7.7-7.85 (2H, m) , 7.97 (IH, d, J=7.7Hz), 8.1
(IH, d, J=7.7Hz), 8.31 (IH, s), 10.13 (IK, s)
Preparation 90
To a solution of 3-bromobenzaldehyde (1.25 g) and
l-methyl-4-tri-n-butylstanniopyrazole (3.0 g) was added
tetrakis (triphenylphosphine) palladium (0) (234 mg). Then
the mixture was heared for 4 hours at 140''C. After
cooling, the reaction mixture was diluted with toluene (16
ml). .zin aqueous solution (14 ml) of potassium fluoride
(4.7 g) was added to zhe mixture and stirred for one hour.
InsoluDle material was filtered off. The filtrate was
35 washed with water and brine, dried over magnesium sulfate.
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25
30
35
- 87 -
and evaporated in vacuo. The residue was chro.atographed
n s ^^^^^^^ ^^^^ _ .^^^^^^ J
'° ^^"^ ^-'^--thylpyrazol-4-yl)i.enzaldehyde (978.1
5 IR (Neat) : 2943, 2818, 1686, 1608, 1230, 1174 cm"!
(CDCI3, 5) : 3.98 (3H, s), 7.4 7-7.58 (IH, J
7-65-7.78 (3H, m) , 7.83 (IH, s), 7.93-7.98 (IH
m) , 10.04 (IH, s)
APCI-MASS (m/z) : 187 (M+H+)
)
TO a solutxon of 3- [ (E) -3-dxmethylan.inopropenoyl ] -
benzon.trile (8 g, ,n acetic acid (80 .1, .,3 added
^nethylhydraexne (2.23 .1). The .ixtu.e was stirred for 3 5
hours at roo. temperature. To the solution was added 5N-
sod... ^^^^^^^^ ^^^^^ ^^^^ N
ce coolxng and extracted with ethyl acetate. The organic
layer was washed with saturated sodxun. bicarbonate
solutxon, water, brine, drxed over n^agnesiun. sulfate
evaporated in vacuo. After chromatography on sxlxca'ge^
(e.utmg with di chloromethane-methanol ) , 3-(i-
methylpyrazol-3-yl)benzonitrile (4.45 g, and 3-(i
-ethylpyrazol-5-yl)benzonitrile (2.09 g, were obtained.
3- (l-Methylpyrazol-3-yl)benzonitrile;
mp : 97-9g°c
IR (KBr) : 3115, 2935, 2220, 1602, 1471, 1352,
1246 cin~l
NMR (CDCI3, 5) : 3.97 (3H, s), 6.56 (IH, d, J=. 3H. ,
7.37-7.60 (3H, m) , 7.95-8.10 (2H, m)
APCI-MASS (m/z) : 134 (M+H+)
3-(l-Methylpyrazol-5-yl)benzonitrile;
mp : 95-97°C
IR (KBr) : 3066, 2951, 2231, 1475, 1416, 1335,
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1236 cm^
NMR (CDCI3, 6) : 3.92 (3H, s), 6.37 (IH, d, J=1.5Hz),
7.50-7.75 {5H, m)
APCI-MASS {m/z) : 184 (M+H"^ )
5
P-re^ppLTritAon 92
A mixture of 3- (broraoacetyl) benzonitrile (38.2 g) and
formamide (190 ml) was heated for 30 minutes at 185°C and
cooled to room temperature. The m.ixture was poured into
10 saturated sodium bicarbonate solution (400 ml) and
extracted with ethyl acetate (1.8 C) • The organic layer
was washed with water and brine, dried over magnesium
sulfate. After evaporation to 200 ml, the resulting
precipitate was collected by filtration, washed with ethyl
15 acetate - isopropyl ether (2:1) to give 3- ( imidazol-4-
yl ) benzonitrile (13.3 g).
mp : igO-lDl-C
IR (KBr) : 2250-3240 (br) , 2224, 1606, 1477, 1333,
1070, 970, 824, 789 cm"^
20 NMR (DMSO-dg, 5) : 7.50-7.68 (2H, m) ,
m) , 8.05-8.20 (2H, m) , 12.32 (IH, br)
APCI-KASS (m/z) : 170 (M+H"^ )
Preparation 93
25 To a solution of methyl 4- f ormylbenzoate (5.0 g) in
ethanol (50 ml) was added sodium borohydride (576 mg)
carefully at 0-5°C and stirred for 30 minutes. The mixture
was poured into water and extracted with dichloromethane .
The organic layer was washed with water and brine, dried
30 over magnesium sulfate, evaporated in vacuo to give methyl
4-hydroxymethylbenzoate (5.06 g) .
IR (KBr) : 2750-3670 (br), 1722, 1614, 1437, 1286,
1111, 1047, 1016, 756 cm."^
NMR (CDCI3, 5) : 1.89 (IH, t, J=5.9Hz), 3.92 (3H, s),
35 4.77 (2H, d, J=5.9Hz), 7.37-7.50 (2K, m) , 7.97-
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8-10 (2H, m)
APCI-MASS (m/z) : 167 (M+H+)
5 1° " -"l-^tion of n,ethyl 4-hydroxymethylbenzoate ,5 0
9> and imidazole ,4.1 g, in N,N-dimethylforma:nide ,25 :nM
was added tert-butyldi^ethylsilyl chloride ,4 77 a)
carefully at O-S-c and stirred for 2 hours at rooj
10 hydrochloric acid ,100 Ml, and extracted with ethyl
acetate. The organic layer was washed with water and
brine, dried over magnesi™ sulfate, evaporated in vacuo to
.ive Methyl - -tert-butyldiMethylsilyloxyMethyl.benzoate
[a .43 g) .
IR (Neat)
2954, 2859, 1724, 1464, 1281, 1107,
841 cm~l
NMR (CDCI3, 5) : 0.11 (6H, s), 0.95 (9H, s), 3 9^
s), 4.79 (2H, s), 7.34-7.44 (2H, xn) , 7 95-
8.05 (2H, m)
20 APCI-MASS (n/z) : 281 (M+H^)
Pren^r^ Mnn Q
°" "^^^^^ ^-^tert-butyldi.ethyls.lyloxy-
25 '^-^ ^) and hydrazine .onohydrate (0.87 .1 )
xn ethanol (0.8 :nl ) was refluxed for one hour After
coolxng to room temperature, the reaction mixture was
poured into water and extracted with ethvl acetate The
organrc layer was washed with water and brrne, drxed over
magnesxum sulfate, evaporated in vacuo to grve [.-(te^t-
--0 ^^Wdimethylsilyloxymethyl) benzoyl] hydrazine (1.0 g)'
mp : 83-85''C
IR (KBr) : 3273 (br) , 2954, 2858, 1662, 1599, 1539,
1335, 1254, 1093, 841 cm-^
NMR ,DMSO-d„ 5, : 0.08 ,6H, s> , 0.91 o„. ,
(2H, S), 4.75 ,2H, s> , 7.30-7.40 ,2K, m, , 7.75-
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7.85 (2H, m) , 9.72 (IH, s)
APCI-MASS (m/z) : 281 (M+H"*")
Preparation 96
5 To a mixture of [ 4- ( tert-butyldimethyls ilyloxymethyl ) -
benzoyl ] hydrazine (8.0 g) and ethyl
acet imidate-hydrochloride (4.24 g) in ethanol (160 ml) was
added triethylamine ( 4 . B ml ) at room temperature and
stirred for 30 minutes. The reaction mixture was
10 evaporated in vacuo. Then the residue was dissolved in
ethyl acetate (120 ml), washed with water and brine. The
organic layer was dried over magnesium sulfate, evaporated
in vacuo. And the residue was heated for 10 minutes at
200°C, cooled to room temperature, chromatographed on
15 silica gel (200 g, eluting with n-hexane - ethyl acetate
(2:1)) to give 2- [4- (tert-butyldimethylsilyloxymethyl ) -
phenyl ] -5-methyl-l , 3, 4-oxadiazole (6.35 g) .
mp : 62-65°C
IR (KBr) : 2956, 2933, 2897, 2860, 1576, 1502, 1257,
20 1086, 843 cm~-
NMR (DMSO-dg, 5) : 0.10 (6H, s), 0.92 (9K, s), 2.56
(3H, s), 4.80 (2H, s), 7.45-7.55 (2H, m; , 7.90-
8.00 (2H, m)
APCI-MASS (m/z) : 305 (M-^H"^)
25
Preparation 97
To a solution of 2- [ 4- ( tert-butyldimethylsi lyloxy-
methyl) phenyl] -5-methyl-l, 3, 4-oxadiazole (2.0 g) in
methanol (20 ml) was added IN hydrochloric acid (13 ml)
30 dropwise at 0-5°C and stirred for one hour. The reacrion
mixture was recooled ro 0-5°C, and sodium bicarbonate (i.l5
g) was added thereto carefully. The mixrure was extracted
with dichloromethane, washed with water and brine, dried
over magnesium sulfate, evaporared in vacuo. The resulting
35 precipitate was collected by filtration ana washed with
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n-hexane to give 2- M-hydroxymethylphenyl, -5-„,ethvI ,1 , .
oxadiazole (0.75 g) . y ' ^ ^ecnyl- ( i , 3, 4
" ■ -i^- ^s.e.
1257, 1053, 833, 729 cm"!
NMR ,D„SO-d„ 5, : 2. SB ,3„, s,, 4.59
T'T:l' ^-^"^--^^ "K
m), 7.87-7.57 (2H, n)
APCI-MASS (m/z) : 191 ^m+.H^)
A mixture of 7 - \ d- 1 r r^yi- k,,- -1 ■
p.enyi,-5-.e...yi-,-3,'.:::: ; ;r :T:trrr-™"'^^--
.1, was heated .o. 2 drop, at 150-C ' .."/^"T'^'"^''-
roon, te»,perature, the Mixture was chroM,t ""^ ^"^ '°
oel (9^n , ^"i^omatographed on silira
!! /' ^'"'^"^ ^-^^-°-thane-.ethanoI (20 i
phenyl] -5-methvl-.H- 2 ^-tri./^ "^J^^y^^^lyioxymethyl ) -
-^1 -/ -^-triazole (5.04 g) .
mp : 90-92 "c
<KBr, : 2953, 2929, 2885, 2354, 1524, 1460, 1431
1255, 1101, 1003, 635 cm-l
--3. 5) : o.oa (.H, s;, 0.9; .9H, 3,, 2.37
(2H, m), 7.27-7.55 (7H, m)
APCI-MASS (m/2) : 394 (M+K^)
^^^-O^r^^tir^^ QQ
_ TO the solution of «-cyclohept yl- 4- ( 4 -benz v> -5-Me th V
4--— 2,4-tr.azol-3-yl,t,enzylar„.ne ,500 „g, in r^'J '
ml). The mixture was stirred tor 4.5 hours at th
room temperature. Palladium Blac. was removed . ^
nitration. The filtrate was basified with IN s;.iu„
h.vdroxide agueous solution under ice cooling anr"
vacuo to dry.ness. The residue was dilutld
dichloromethane-methanol ,5:1,, dried over magnesium
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sulfate, evaporated in vacuo. After chromatography on
silica gel (15 g, eluting with dichloromethane-methanol
(4:1)) N-cycloheptyl-4- { 5-methyl-4H- 1 , 2, 4-tria2ol-3-
yl ) benzylamine (219.6 mg) was isolated.
5 IR (KBr; : 2500-3700 (br) , 2926, 2854, 1564, 1458,
1099 citi"^
NMR (CDCI3, 6) : 1.30-2.00 (12H, m) , 2.48 (3H, s),
2.65-2.80 (IH, m) , 3.83 (2H, s), 4.60-5.15 (2H,
br), 7.30-7.40 (2H, m) , 7.90-8.00 (2H, m)
10 APCI-MASS (m/z) : 285 (M+H"^)
Prf'n^^iration 100
To the solution of 3- ( IH-tetrazol- 5-yl ) benzaldehyde
(600 mg) in N, N-dimethylf ormamide ( 6 ml ) was added sodium
15 hydride (60's oil suspension, 138 mg) at 0-5°C. After
stirring for 15 minutes, to the mixture was added methyl
iodide (0.43 ml) . The solution was stirred for 3 hours at
room temperature, then stirred for 30 minutes at 40°C. The
reaction mixture was poured into water and extracted with
20 ethyl acetate, washed with water and brine, dried over
magnesium sulfate, evaporated in vacuo. After
chromatography on silica gel (25 g, eluring with n-hexane -
ethyl acetate (1:1), 3- (2-methyl-2H-tetrazol-5-
yl ) benzaldehyde (510.7 mg) and 3- ( l-methyl-lH-tetrazol-5-
25 yl ) benzaldehyde (81.6 mg) was obtained.
3_ (2-Methyl-2H-tetrazol-5-yl ) benzaldehyde
mp : 9S-99°C
IR (KBr) : 3072, 2839, 1691, 1587, 1520, 1443 cm"^
30 NMR (DMSO-dg, 5) : 4.47 (3K, s), 7.81 (IH, dd, J=7.7,
7.7Hz), 8.05-8.10 (IH, m) , 8.33-8.40 (IH, m) ,
8.55-8.58 (IH, m) , 10.14 (IH, s)
APCI-MASS (m/z) : 189 (M+H"^ )
35 3- (i-Methyl-lH-tetrazol-5-yl ) benzaldehyde
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IR (KBD : 1699, 1608, 1535, 1450, 1394 cm-l
^^^^^^-^6' ■ ^-^-^ ^3H, s), 7.07 a-H, dd, .-7 7
V.7HZ), 8.13-8.25 (2K, 8.38-8.40 (IH, n) , ' '
10.14 (IH, s)
APCI-MASS (m/2) : 189 (M+H+ )
J° the solution of 4-fluoroi,enzaldehyde ,3.0 „ and
w.. added pota.siu. carbonate ,..0 g, . Then the fixture
was heated for one hour at 120-c. After cooling, the
reaction Mixture was diluted „.th ethyl acetate ,300 nl,
washed w.th water, brine, dried over .agnesiu. sulfate L
h^".'^^"°- -nected and
mp : 147-148°C
IR (KBr) : 3130, 2856, 1709, 1603, 1518, 1441
1275 cm-l
'"^^^3^ 5) : 7.88-8.01 (2H, m) , 8.01-8.14 (2H
m), 8.16 (IH, s), 8.70 (l.H, s), 10.07 (1h s)'
APCI-MASS (m/2) : 174 {M-H+)
15
25
30
J° ^ -^-t-- °^ 4-fluorobenzaldehyde (5.0 g) and l'.-
l,2,3-trxa2ole (3.33 g) in N, N-dimethyl formaxn.de (50 .1. '
was added potassium carbonate (6.68 g) . Then the mix'^u^e
was heated for one hour at 120'C. After cooling the ^ '
reaction mixture was diluted with ethyl acetate '(300 ml)
washed with water, brine, dried over magnesium sulfate a^d
evaporated to about 50 ml m vacuo. The resulting
precipitate was collected by filtration, washed with
hexane to give 4 - ( lH-1 , 2 , 3-triazol-l- vM x.en- - i h«h w 7.
, y- -J^'en^aldehvde (3.^4
g. - The mother liquid was evaporated to abou^ lo"n' .
vacuo. The resulting precipitate was also collected the
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similar procedure as mentioned above to give 4-(2H-l,2,3-
triazol-2-yl) benzaldehyde (297 mg) .
4- (lK-1, 2, 3-Triazol-l-yl) benzaldehyde
5 IR (KBr) : 3138, 3116, 2845, 1695, 16G3, 1516, 1419,
138 9 cm"-
NMR (CDCI3, 5) : 7.91 (IH, s), 7.93-8.11 (4H, m) ,
8.12 (IH, s), 10.09 (IH, s)
APCI-MASS (m/z) : 174 (M+H"^)
10
4- (2H-1, 2, 3-Triazol-2-yl) benzaldehyde
IR (KBr) : 3114, 3084, 2715, 1699, 1603, 1508, 1408,
13 83 cm"l
NMR (CDCI3, 5) : 7.89 (2H, s), 7.95-8.06 (2H, m) ,
15 8.23-8.33 (2K, m) , 10.06 (IH, s)
APCI-MASS (m/z) : 174 (M+H"*")
Preparation 103
To a solution of 4-f luorobenzaldehyde (6.21 g) in
20 N, N-dimethyl f ormamide (100 ml) were added
1 1-methylpiperazine (6.01 g) and powdered potassium
carbonare (8.29 g), and the mixture was stirred at 150°C
for 4.5 hours under nitrogen. The mixture was poured into
a mixture of ethyl acetate and ice water, and the separated
25 organic layer was washed with water and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give 4-
( 4-me-chylpiperazin-l-yl) benzaldehyde (5.31 g) as a yellow
solid .
30 IR (KBr) : 2935, 2840, 2790, 2750, 1690, 1600, 1560,
1520 cm"l
NMR (DMSO-dg, 5) : 2.22 (3H, s), 2.4-2.5 (4H, m) ,
3.35-3.45 (4H, m) , 7.04 (2H, d, J=8.8Hz), 7.7C
(2H, d, J=8.8Hz), 9.71 (IK, s)
35
wo 96/10559
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15
20
- 95 -
To a solution of 4-bromoanxline (6.88 g) m pyridine
(20 ml) was added dropwise methanesul f onyl chloride (4 58
g) at 5'C and the mixture was stirred at 5'C for 1.5 hours
and at room temperature f or 1 . 5 hours. The mixture was
poured into a mixture of ethyl acetate and dilute
hydrochloric acid and the insoluble materials were filtered
Off. The filtrate was separated and the organic layer was
washed with brine, dried over magnesium sulfate and
10 evaporated in vacuo. The residue was crystallized and the
crystal was collected by filtration, washed with
diisopropyl ether and dried to give 4-bromo-N-
methylsulfonylaniline (8.30 g) .
IR (KBr) : 3290, 1490 cm"!
NMR (DMSO-dg, 5) : 3.00 (3H, s), 7.16 (2H, d,
J=8.7H2), 7.52 (2H, d, J=8.7H2), 9.92 (IH, br)
Prenarqtinn ]n<^
To a suspension of N-methyl-N-methoxy-4-
sulfamoylbenzamide (3.53 g) and benzoxc- acid (1.95 g)
dxchloromethane (100 ml) were added 4-dxmethylaminopyrxd.ne
a.9D g) and 1- ( 3-dimethylaminopropyl ) -3-ethyl
carbodiimide-hydrochloride (3.07 g)' at room temperature and
-xxture was stirred at the same temperature for 18
hours. The mixture was washed with water and brxne, drxed
over magnesium sulfate and evaporated m vacuo The
residue was purified by column chromatography on silica gel
to give N-methyl-N-methoxy 4- (N-benzoylsulf amoyl", benzamide
(1.35 g j .
^-^S^' ■■ 3072, 2970, 2937, 1649, 1597, 1560,
1544 cm~l
NMR (DMSO-dg, 6) : 3.27 (3K, s), 3.55 (3H, s), 7.35-
7-5 (3K, m), 7.68 (2H, d, J=8.2Hz), 7.85-7.95
(2H, m), 7.96 (2H, d, J=8.2Hz)
APCI-MASS (m/z) : 349 (M+H+)
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Preparation 106
To a suspension of 4-cyanobenzaldehyde (26.23 g) was
added carefully sodium borohydride (3.78 g) at room
temperature, and the mixture was stirred at the same
5 temperature for 2 hours. The mixture was evaporated in
vacuo and the residue was extracted with dichloromethane .
The organic layer was washed with brine, dried over
magnesium sulfate and evaporated in vacuo to give crude
4-cyanobenzyl alcohol (24.97 g) as an oil.
10 IR (Film) : 3419, 2916, 2875, 2229, 1610 cm"^
NMR (CDCI3, 5) : 2.07 ( IH, br) , 4.79 {2H, br s) , 7.48
(2H, d, J=8.1H2), 7.65 (2H, d, J=8.1Hz)
APCI-MASS (m/z) : 134 (M+H+ )
15 Preparation 107
To a solution of 4-cyanobenzyl alcohol (24.96 g) in
N, N-dimethylf ormamide (100 ml) were added imidazole (16.0
g) and tert-butyldimethylsilyl chloride (31.0 g) at room
temperature and the mixture was stirred for 2 hours. The
20 mixture was poured into a mixture of ethyl acetate and ice
water, and the separated organic layer was washed with
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel zo give 4-(tert-
25 butyldimethylsilyloxymethyl ) benzonitrile (40.78 g) as an
oil .
IR (Film) : 2954, 2429, 2885, 2858, 2229, 1610 cm" -
NMR (CDCI3, 5) : 0.11 (6H, s), 0.95 (9H, s), 4.79
(2H, S), 7.43 (2H, d, J=8.3Hz), 7.63 (2H, d,
30 J=8.3Hz)
APCI-MASS (m/z) : 248 (M+H"^ )
35
Prepara tion 108
To a solution of n-butyllithium (1.71M hexane
solution, 58.5 ml) in diethyl ether (150 ml) was added
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0
aropwise 3-bromopyridine (15.8 g) at 5°c, and the mixture
was stirred at 5°c for an hour. The mixture was cooled to
oCc and a solution of 4- ( tert-butyldimethv ' silyl-
oxymethyDbenzonitrile (19.79 g) in diethyl' ether (80^...
was added dropwise over 1.2 hours under nitrogen. The
mixture was gradually warmed to roo.T. temperature and'"
stirred at the same temperature for additional 2 hours
The mixture was poured into a m.ixture of ethvl acetate and
dilute hydrochloric acid, and the separated organic laye^
was washed with water and brine, dried over magnesium
sulfate and evaporated in vacuo. The residue was our^^-^ed
by column chromatography on silica gel to aive 3-[(4-te>-t-
butyldimethylsilyloxymethyl) benzoyl J pyridine (4.96 a) as a
red oil .
IR (Film) : 3034, 2954, 2930, 2SS5, 2856, 1660, 1608,
1585, 1537 cn~-
NMR (CDCI3, 6) : 0.16 (6H, s), 0.99 (9H, s), 4.87
(2H, s), 7.50 (2H, d, J=7.6Hz), 7.83 {2H, d,
J=7.6Hz), 7.4--7.5 (IH, m) , 8.1-S.2 (IH, m) , ' 8 . 8-
8.9 (IH, n) , 8.99 (IH, d, J=2.1Hz)
APCI-MASS (m./z) :328 (M+K+ )
Preparation 1 ng
To a suspension of 3- [ (4-tert-butyldimethvlsilyloyy-
methyl) benzoyl] pyridine (4.94 g) in ethylene glycol (4o'mi)
were added potassium hydroxide (1.27 g) and hydra^ir^
hydrate (4.84 g) and the mixture was stirred at 150°C fo- 2
hours and at 200»C for 4 hours. The mixture was ooured ^
xnto a m.ixture of ethyl acetate and ice water, and the
separated organic layer was washed with water and brine
dried over magnesi-om sulfate and evaporated m vacuo. The
residue was purified by column chromatography on silica gel
to give 4- (3-pyridylmethyl) benzyl alcohol (I.2
orange oil.
The
ca
o g) as an
:R (Film) : 3323, 3030, 2920, 2868, 1579, 1549,
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1514 cm~^
NMR CCDCI3, 5) : 1.85 (IH, br), 3.97 {2H, s), 4.67
;2H, s), 7.15-7.5 {6H, , 8.45-8.55 (2H, m)
APCI-MASS (m/z) : 2CC (M+h")
. 5
p^c.p^ra1-i nn 110
To a solurion of 4 -( 3-pyridylmethyl) benzyl alcohol
(1.26 g) in chloroform (30 mi) v/as activated manganese
dioxide (5.50 g) and the mixture was refluxed for 2 hours.
10 Manganese dioxide was removed off and the filtrate was
evaporated in vacuo and the residue was purified by column
chromatography on silica gel to give 4- ( 3-pyridylmethyl ) -
benzaldehyde (1.09 g) as an orange oil.
IR (Film) : 3029, 2989, 2910, 2831, 2738, 1697, 1599,
15 1510 cm"-
NMR (CDCI3, 5) : 4.07 (2H, s), 7.24 (IH, dd, J=7.8,
4.8KZ), 7.35 (2H, d, J=8.1Hz), 7.47 (IK, dd,
J=7.8, 1.4Hz), 7.83 (2H, d, J=8.1Hz), 8.49 (IH,
d, J=1.4Hz), 8.51 (IH, s), 9.99 (IH, s)
20 APCI-MASS (m/z) : 198 (M+H+)
Preparat ion 111
To a solution of l-ethoxycarbonyl-4-diethylphosphono-
1, 4-dihydropyridine (34.71 g) in tetrahydrof uran (200 ml)
25 was added dropwise n-buryllirhium (1.71M hexane solution,
70.2 ml) at -60°C over 30 minutes under nitrogen, and the
mixture was stirred at -60°C for 40 minutes. To this
solution was added dropwise a solution of 4-cyanobenzyl
bromide (27.40 g) in tetrahydrof uran (80 m.l ) at -60°C and
30 the mixture was gradually warmed to room temperature and
stirred for 21 hours. The mixture was poured into a
mixture of ethyl acetate and dilute hydrochloric acid, and
the separated organic layer was washed with water and
brine, dried over magnesium sulfate and evaporated in
35 vacuo. The residue was purified by column chromatography on
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15
silica gel to give l-erhoxycarbonyl-4- (4-cvanobenzyi ) -.-
cllethylphosphono- 1 , 4-dihydropyridine (47.10 g) as a cr-d-
red oil.
IR (Film) : 3053, 2891, 2933, 2903, 2227, 1723, 1689,
• ^ 1626, 1606 cm~-
NMR (CDCI3, 5) : 1.2-1.4 (9H, , 3. 06 (2H, d,
J-7.6H2), 4.1-4.3 (6H, m), 4.7-4.9 (2H, m) ,
7-65-7.9 (2H, ra) , 7.22 (2H, d, J=8.2Hz)', 7^55
(2H, d, J=8.2Hz)
10 APCl-MASS (m/z) : 4 05 (M+H^)
Prpn^r^ tinn 11p
To a solution of l-ethoxycarbonyl-4- ( 4-cvanobenz vl ) -4 -
diethylpnosphono-l,4-dihydropyridine (42.10 g) in
dichloromethane (350 ml) was added dropwise
diisobutylaluiuinum hydride (I.OIM toluene solution 515 n^ii
at -60°C over 55 minutes and the mixture was starred
60-C for 1.5 hours. The mixture was gradually warmed to
5°C and starred ar 5"c for 1.5 hours. To the mixture we^e
adaed sodium fluoride (87.34 g) and water (28.11 g)
mixture was stirred at room temperature for an hou-
insoluble materials were filtered off and washed wi^.
dichloromethane. Tne filtrate was evaporated in vacuo an
the residue was dissolved in tetrahydrof uran (2C0 )
this solution was added 6N hydrochloric acid (30 mM '.z-
rhe mixture was stirred at room temperature for 3 ncu^s
The mixture was adjusted to pK ca . 8 by addition o^" sn '
sodium hydroxide and extracted with dichloromethane. ^h^
organic layer was washed with water and brine, d-ied ove^
nagnesium sulfate and evaporated in vacuo. The residuP^wa^
purified by colum.n chromatography on silica gel to gi.^e
4- (4-pyridylmethyl)benzaldehyde (4.62 g) as a red oil '
IR (Film) : 3381, 3053, 3030, 2924, 283l" 2738,^'l697,
1606, 1576 cm~l
35 NMR (CBCI3, 5) : 4. 08 (2H, s), 7.1-7.2 (2K,
20
25
30
and tne
To
ml ) and
m; ,
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- 100 -
7.3-7.45 (2H, m) , 7.8-7.9 (2K, m) , 8.5-8.6 {2H,
m) , 10 . 00 (IK, s)
Preparation 113
5 To a solution of pyrazole (1.67 g) in
N, N-dimethyl f ormamide (30 ml) was added sodium hydride (60~2
oil suspension, 950 mg) at 0-5°C. After stirring for 30
minutes, to the mixture was added a solution of
4-bromomethylbenzonitrile (4.0 g) in N, N-dimethylf ormamide
10 (10 ml) dropwise under ice cooling, and the mixture was
stirred for two hours at room temperature. The reaction
mixture was diluted with ethyl acetate (240 ml), washed
with water and brine, dried over magnesium sulfate,
evaporated in vacuo. The residue was chromatographed on
15 silica gel (100 g, eluting with n-hexane - ethyl acetate
(1:1)) to give 4- (pyrazol-l-ylmethyl ) benzonitrile (3.49 g) .
mp : 80-81°C
IR (KBr) : 3055, 2958, 2229, 1610, 1510, 1446, 1392,
1275 cm~-
20 NMR (CDCI3, 5) : 5.39 (2H, s), 6.33 (IH, dd, J=2.1,
2.1Hz), 7.18-7.30 (2H, m) , 7.44 (IH, d, J=2.1Hz),
7.55-7.70 (3H, m)
APCI-MASS (m/z) : 184 (M+H"^)
2 5 Preparation 114
To a solution of imidazole (1.67 g) in
N, N-dimethyl f ormamide (30 ml) was added sodium hydride (60-,
oil suspension, 950 mg) at 0-5°C. After stirring for 30
minutes, to the mixture was added a solution of
30 4-bromomethylbenzonitrile (4.0 g) in N, N-dimethyl f ormamide
(10 ml) dropwise under ice cooling, and the mixture was
stirred for two hours at room temperature. The reaction
mixture was diluted with ethyl acetate (240 ml], washed
with water and brine, dried over magnesium sulfate,
35 evaporated in vacuo. The residue was chromatographed on
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(15:1)
g)
^ — m.
to gxve '^-(iniidazol-l-yixnethyDbenzonitrile
(3.2
10
IR ,KBr, : 3095, 3057, 2229, 1608, 1510, 1,25, 1236
1074, 731 cm-1
NMR ,CDCl3, 6, : 5.21 ,2K. s,, 6.90 (IH, s), 7 1.
^-^^-^-^^ <^H, 7.57 ,1H, s>, 7.60-
7.72 (2H, m)
APCI-MASS (m/z) : 184 (M+H^)
?:reparatinn
ac.d ,10.0 g) ,n :„ethancl ,100 n.1, were added scd^urr,
stxrred at roo. temperature for 35 .mutes. The Mixture
"as evaporated In vacuo and dried thoroughly. The 3odru„
=a t .3pended in petroleu. ether ,60 .1^ and iToZ,
c lor de 30.93 g; „as added thereto and the „.«ure was
Stirred at room temperature for 16 hours Th^ .
- evaporated in vacuo and the residue was redrsL::::""
petroleum ether ,200 ml,. The insoluble materials we're
entered off and the filtrare was evaporated i„ vacuo to
give 3,S-di-tert-butyl-4-hydroxybenzoyl chloride ,9 8- „,
as a yellow solid. ' ~ "
IR (KBr, : 355., 297.. 2956, 1736, 1597, 1574 cm-^
Prer,aratj»n 11^
To a solution of sodium azide ,4.61 g, ,n wa'e- ,30
30 Tl " °' 3,5-dx-tert-;u;yl-4-
hydroxyben.oyl chloride ,12.72 g, in tetrahydrof uran ,60
m., at 5 c over 30 minutes, and the fixture was strrred at
5 . for 1.5 hours. The mixture was extracted with ethyi
acetate, and the organic layer was washed wrth brine, d'-^ed
over magnesxum sulfate a.nd evaporated in vacuo. To f-e"
residue was added .n-.hexane ,60 mi, and the insoluble "
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materials were filtered off. The filtrate was evaporated
in vacuo to give 3 , 5-di-tert-butyl-4-hydroxybenzoyl azide
(1.49 g) as a yellow solid.
IR (KBr) : 3593, 2966, 2912, 2873, 2141, 1668,
5 1599 cm~^
Preparation 117
A suspension of 3 , 5-di-tert-butyl-4-hydroxybenzoyl
azide (1.49 g) in benzene (30 ml) was refluxed for an hour
10 under nitrogen. To the mixture was added tert-butanol
(4.01 g) and the mixture was refluxed for 3 hours. The
mixture was evaporated in vacuo and the residue was
purified by column chromatography on silica gel to give
N-tert-butoxycarbonyl-3, 5-di-tert-butyl-4-hydroxyaniline
15 (1.17 g) as a white solid.
IR (KBr) : 3647, 3331, 2958, 2913, 2873, 1693, 1606,
1547 cm'l
NMR (DMSO-dg, 5) : 1.34 (18H, s), 1.44 {9H, s), 6.60
(IH, s), 7.22 (2H, s) , 8.84 (IH, br s)
20
Preparati on 118
To a solution of N-tert-butoxycarbonyl-3, 5-di-tert-
butyl-4-hydroxyaniline (3.97 g) in ethyl acetate (60 ml)
and ethanol (15 ml) was added 4N hydrochloric acid in ethyl
25 acetate (30.8 ml) and the mixture was stirred at room
temperature for 24 hours. The mixture was evaporated in
vacuo and the residue was triturated with diisopropyl
ether. The powder was collected by filtration, washed wiuh
diisopropyl ether and dried in vacuo to give 3, 5-di-tert-
30 butyl-4-hydroxyaniline-hydrochloride (2.85 g) .
IR (KBr) : 2966, 2912, 2873, 2590, 1581, 1512 cm" ^
NMR (DMSO-dg, 5) : 1.38 (18H, s), 7.12 (2H, s),
7.34 (IK, s) , 9.83 {2H, br si
35
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- 103 -
To a suspension of 4-f ormylbenzoic acid n . .
i-hydroxybenzotriazole (1.49 g) in dxchl
5 was added 3- ( 3-dimeth v J. ■ ^^^hloromethane (60 n.1 )
(. 71 a) .^ ^^'^^'^°P^°-°-^^^-l-^t:hylcarbodiin.ide
(--VI g) at room temperature and the resuJtin
stirred at th^ resulting solution was
cirred at the same temperature for 20 hours Th. • .
was washed with water and brine dried '
sulfate and evaporated in vac: ! h .eTL^r^^^^^^-
' column chromatography on s.l.ca ..^Z^X::: U^^^T
tert-utyl.hydroxyphenyl,carbamoyl.ben.aL^^^^
(KBr) : 362., 3286, 2958, 2912, 2872, 1703, 1645
1606, 1547 cm-i
J=5.1H.,. 7.09 ,2H, d. J.5.1HZ,, 7.12 ,2H,' 3,
10-0^ (IH, S), 10.19 ,1H, s,
APCI-MASS (m/z) ;
^'^'•"'"-I'-i -n ipr
To a suspension of 4-foraylben2oic acid ,7 =, „, ■
d.c..loro.etha„e ,25 .1, „ere added tMon^ l J; ,: .i^: ,
. and „,N-d..e...l,o..a„.de ,3es a/.oo. .e pe. ^
and the ..xtura was .efluxed for 4 hours under nitrogen
The Mixture was evaporated in vacuo and dried r„ v„ "
..ve^crude 4-f or..l.en.o.l chloride ,e.S3 .ras^aTrrtV"
IR (KBr, : 3066, 2856, 1745, 1691, 1576, 1504 c."!
To a solution of 4 -f luoroanil ine (5.0 g, and
^rxethylanine <6.07 g, m dichloroMethane ,60 „M was add .
Portronwise 4-for.ylbenzoyl chloride ,8.53 g, at 5" h
the mixture was sn ^^^^ * ' -^J g» at 5 ^ and
TV, . stirred at room temperature for 2 hours
The mxxture was washed with water and brrne dried oT
.agnesium sulfate and evaporated in vacuo, '.hi M:::;
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crystallized from hexane - ethyl acetate (3:1) and
collected by filtration, washed with hexane - ethyl acetate
(3:1) and dried in vacuo to give 4- [N- (4-f luorophenyl ) -
carbamoyl ] benzaldehyde (4.58 g) .
5 IR (KBr) : 3356, 2872, 1703, 1651, 1606, 1537,
1514 cm~l
NMR (DMSO-dg, 6) : 7.15-7.3 (2H, m) , 7.8-7.9 (2H, m) ,
8.06 (2H, d, J=8.4Hz), 8.14 (2H, d, J=8.4Hz),
10.12 (IH, s), 10.53 (IK, br s)
10 APCI-MASS (m/z) : 244 (M+H"^)
Preparation 122
To a suspension of sodium hydride {SO'l oil dispersion,
4 64 mg) in N, N-dimethylf ormamide (50 ml) was added dropwise
15 a solution of 4- [N- (4-fluorophenyl) carbamoyl ] benzaldehyde
(2.63 g) in N, N-dimethyl f ormamide (40 ml) at 5°C under
nitrogen, and the mixture was stirred at room temperature
for an hour. To the mixture was added methyl iodide (3.29
g) , and the mixture was stirred at room temperature for 3
20 hours. The mixture was poured into a mixture of ethyl
acetate and ice water. The separated organic layer was
washed with water and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purified by
column chromatography on silica gel to give 4-[N-(4-
25 fluorophenyl ) -N-methylcarbamoyl ] benzaldehyde (2.24 g) as an
orange oil .
IR (Film) : 3068, 2981, 2939, 2839, 2737, 1703, 1639,
1608, 1571, 1510 cm"^
NMR (DMSO-dg, 6) : 3.37 (3H, s), 7.05-7.2 (2H, m) ,
30 7.25-7.35 (2H, m) , 7.46 (2H, d, J=8.1Hz), 7.77
(2H, d, J=8.1Hz), 9.93 (IH, s)
APCI-MASS (m/z) : 258 (M+H"^)
Preparation 123
55 To a solution of 1 , 4-bis (hydroxymethyl ) benzene (25.72
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- 105 -
g) in N,N-dimethylformamide (300 ml) were added imidazole
(15.21 g) and tert-butyldimethylsilyl chloride (28.06 g) at
room temperature, and the mixture was stirred for 10 hours
The mixture was poured into a mixture of ethyl acetate and
5 ice water, and the separated organic layer was washed with
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give 4-(tert-
butyldimethylsilyloxymethyl) benzyl alcohol (27 89 g) as an
10 oil.
IR (Film) : 3352, 2954, 2931, 2887, 2858, 1541, 1514,
14 66 cm~^
NMR (DMSO-dg, 5) : 0.07 (6H, s) , 0.90 (9H, s), 4.47
(2H, d, J=5.7H2), 4.68 {2H, s), 5.10 (IH, t,
J=5.7Hz), 7.2-7.3 (4H, m)
Prenaratioy^ t ?4
To a solution of 4- ( tert-butyldimethylsilyloxymethyl ) -
benzyl alcohol (27.86 g) in chloroform (300 ml) was added
20 activated manganese dioxide (47.98 g) and the mixture was
refluxed for 3.5 hours. Manganese dioxide was filtered off
and the filtrate was evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give 4-
(tert-butyldimethylsilyloxymethyl)benzaldehyde (26.86 g) as
25 a pale yellow oil.
IR (Film) : 2955, 2931, 2889, 2858, 2731, 1703,
1608, 1578, 1541 cm~^
NMR (DMSO-dg, 5) : 0.10 ( 6H, s), 0.92 (9K, s), 4.82
f2H, s), 7.53 (2H, d, J=8.2Hz), 7.89 {2H, d,
J=8.2Hz), 9-99 (IH, s)
30
To a solution of N-cycloheptyl-4- (tert-
butyldimethylsilyloxymethyl) benzylamine (53.74 g) in
35 methanol (250 ml) was added dropwise cone, hydrochloric
PCT/JP95/01982
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- 106 -
acid (38.6 ml) at 5°C, and the mixture was stirred at room
temperature for 3 hours. The mixture was evaporated in
vacuo and the residue was pulverized with tetrahydro f uran
and ethyl acetate. The powder was collected by filtration,
5 washed with ethyl acetate and tetrahydro f uran and ethyl
acetate (1:1), and dried in vacuo under phosphorus
pentoxide to give N-cycloheptyl-4-
hydroxymethylbenzylamine-hydrochloride (37.92 g) .
IR (KBr) : 3294, 2927, 2858, 2791, 1578, 1541, 1514,
10 14 56 cm"-'-
NMR (DMSO-dg, 5) : 1.4-2.2 (12H, m) , 3.05-3.25 (IH,
m) , 4.12 (2H, s), 4.52 (2H, d, J=5.7Hz), 5.27
(IH, t, J=5.7HZ), 7.36 (2H, d, J=8.0Hz), 7.48
(2H, d, J=8.0Hz), 8.7-8.9 (IH, br)
15 APCI-MASS (m/z) : 234 (M+H"^-HC1)
Preparat -ion 126
To a suspension of N-cycloheptyl-4-
hydroxymethylbenzylamine-hydrochloride (37.9 g) in
20 chloroform (400 ml) were added activated manganese dioxide
(50.86 g) and triethylamine (14.21 g), and the mixture was
refluxed for 4 hours. Manganese dioxide was filtered off
and the filtrate was washed with water and brine, dried
over magnesium sulfate and evaporated in vacuo. The
25 residue was purified by column chromatography on silica gel
to give N-cycloheptyl-4-f ormylbenzylamine (18.27 g) as a
ye 1 low oil.
IR (Film) : 3051, 2924, 2854, 2731, 1701, 1606, 1575,
14 68 cm~^
30 NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.0-2.2 (IH,
br) , 2.5-2.7 (IH, m) , 3.77 (2H, s), 7.56 (2H, d,
J=8.1Hz), 7.85 (2H, d, J=8.1Hz), 9.97 (IH, s)
APCI-MASS (m/z) : 232 (M+H+)
35
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15
- 107 -
To a solution of N-cycloheptyl-4-f ormylbenzylamine
(18.26 g) in ethanol (200 ml) were added thiazolidin 2 ^-
dione (9.25 g) and piperidine (6.72 g) , and the mixturi was
refluxed for 17 hours. The mixture was cooled to 5°C and
the precipitates were collected by filtration, washed with
ethanol and diisopropyl ether and dried in vacuo to give
N-cycloheptyl-4-[(2,4-dioxothiazolidin-5-ylidene)methvll-
benzylamine (9.61 g) as a yellow crystal. The filtrate was
evaporated in vacuo and the residue was purified by column
chromatography on silica gel to give the second crop (4 13
g) .
IR (KBr) : 3429, 3024, 2929, 2858, 1684, 1622, 1576,
1547, 1458 cm~l
NMR (DMSO-dg, 5) : 1.3-2.2 (12H, m) , 3.05-3.25 (IH,
m), 4.12 (2H, s), 7.35 (IH, s), 7.52 (2H, d,
J=8.5Hz), 7.58 (2H, d, J=8.5H2)
APCI-MASS (m/z) : 331 (M+H+)
2 0 Prepar^l- ion
To a suspension of N-cycloheptyl-4- [ (2, 4-
dioxothiazolin-5-ylidene)methyl]benzylamine (13.61 g) in
tetrahydrofuran (300 ml) and methanol (300 ml) was added 5'
sodium-amalgam (56.8 g) , and the mixture was stirred at
25 room temperature for 24 hours. The insoluble materials
were removed by filtration on celite and the filtrate was
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give N-cycloheptyl-4- [ (2, 4-
dioxothiazolidin-5-yl)methyl]benzylamine (5.84 g) as a
30 yellow solid.
IR (KBr) : 3028, 2933, 2862, 2764, 1674, 1630, 1581,
14 60 cm~^
NMR (DMSO-dg, 6) : 1.3-2.2 (12H, m) , 2.9-3.1 (IH, m) ,
2-95 ilH, dd, J=13.8, 9.3Hz), 3.36 (IK, dd,
J=9.3, 4.0Hz), 4.54 (IH, dd, J=9.3, 4.0Hz),' 7.25
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(IH, d, J=8.1Hz), 7.38 {IH, d, J=8.1Hz)
APCI-MASS (m/z) : 333 (M+H"^)
Preparation 129
5 To a solution of 4-f luorobenzaldehyde (20.11 g) and 4-
chlorophenol (25.0 g) in N, N-dimethylf ormamide (250 ml) was
added powdered potassium carbonate (26.81 g), and the
mixrure was stirred at 150°C under nitrogen for 7 hours.
The mixture was cooled and poured into a mixture of ethyl
10 acetate and water. The separated organic layer was washed
with water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give 4-(4-
chlorophenoxy) benzaldehyde (32.49 g) as a yellow oil.
15 IR (Film) : 3070, 2985, 2830, 2740, 1735, 1695, 1605,
1580, 1485 cm"^
NMR (CDCI3, 5) : 7.0-7.15 (4H, m) , 7.35-7.45 (2H, m) ,
7.8-7.9 (2H, m) , 9.93 (IH, s)
APCI-MASS (m/z) : 235, 233 (M+H+)
20
Prpnaration 130
To a solution of 4- f luorobenzaldehyde (5 g) and 3-
fluorophenol (5.42 g) in N, N-dimethylf ormamide (50 ml) was
added potassium carbonate (6.68 g) . Then the mixture was
25 heated for 3.5 hours at 150°C. After cooling, the reaction
mixture was diluted with ethyl acetate (300 ml), washed
with water, brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was chromatographed on
silica gel (200 g, eluting with n-hexane - ethyl acetate
30 (10:1)) to give 4- ( 3-fluorophenoxy) benzaldehyde (8.67 g).
IR (Neat) : 3072, 2831, 2738, 1697, 1587, 1483 cm~l
NMR (CDCI3, S) : 6.75-7.00 (3H, m) , 7.05-7.18 (2H,
m) , 7.28-7.42 (IH, m) , 7.82-7.95 (2H, m) , 9.95
(IH, s)
35 APCI-MASS (m/z) : 217 (M+H^)
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10
- 109 -
Preparation
To a solution of 4-f luorobenzaldehyde (3 g) and
4-trifluoromethylphenol (4.7 g) in N, N-dimethylf orznamide
(30 ml) was added potassium carbonate (4.0 g) . Then the
mixture was heated for 5 hours at 150»C. After cooling
the reaction mixture was diluted with ethyl acetate (300
ml), washed with water, brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was chromatographed
on silica gel (200 g, eluting with n-hexane - ethyl acetate
(15:1)) to give 4- (4-trif luoromethylphenoxy) benzaldehyde
(982. 1 mg) .
IR (Neat) : 3074, 2831, 2738, 1701, 1587, 1502 cm"!
NMR (CDCI3, 5) : 7.05-7.25 (4H, m) , 7.60-7.75 (2H,
m), 7.85-7.98 (2H, m) , 9.96 (IH, s)
15 FAB-MASS (m/z) : 267 (M+H+)
Prepar;^tion ]Tp
To a solution of 4-f luorobenzaldehyde (3 g) and 3 4-
methylenedioxyphenol (4 g, in N, N-dxmethyl f ormamxde (30 ml)
20 was added potassium carbonate (4 g) . Then the mixture was
heated for 2 hours at 150-C. After cooling, the reaction
mixture was diluted with ethyl acetate (200 ml), washed
with water, brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was chromatograohed on
s.lxca gel (120 g, eluting with n-.hexane - ethyl acetate
(5:1)) to give 4- (3, 4-methylenedioxyphenoxy) benzaldehvde
(2 . 67 g) .
mp : 65-6 6°C
IR (KBr) : 1691, 1600, 1481, 1227 cm-1
30 NMR (CDCI3, 5) : 6.02 (2K, s), 6.50-6.65 {2H, m) ,
6.82 (IK, d, J=8.3Hz), 6.96-7.07 (2H, m) , 7.78-
"7.89 (2K, m) , 9.91 (IK, s)
APCI-MASS (m/z) : 243 (M+H+)
35
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Pr(^para1-ion 133
To a solution of 4- f luorobenzaldehyde (2.48 g) and
3, 5-di-tert-butyl-4-methoxyinethoxyphenol (5.33 g) in N,N-
dimethylformamide (40 ml) was added powdered potassium
5 carbonate (2.76 g) , and the mixture was stirred at 150°C
for 6 hours under nitrogen. The mixture was poured into a
mixture of ethyl acetate and ice water, and the separated
organic layer was washed with water and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
10 purified by column chromatography on silica gel to give 4-
(3, 5-di-tert-butyl-4-methoxymethoxyphenoxy) benzaldehyde
(4.03 g) as an orange oil.
IR (Film) : 2960, 2872, 2740, 2693, 1581, 1504 cm"-
NMR (CDCI3, 5) : 1.43 (18H, s), 3,66 (3H, s), 4.94
15 (2H, s), 6.99 (2H, s), 7.02 (2H, d, J=8.8Hz),
7.83 (2H, d, J=8.8Hz), 9.92 (IH, s)
APCI-MASS (m/z) : 371 (M+H+)
Pi-aparai-i nn 134
20 To a solution of 4-f luoronitrobenzene (14.11 g) and 4-
fluorophenol (12.33 g) in N, N-dimethylf ormamide (150 ml)
was added powdered potassium carbonate (15.20 g) , and the
mixture was stirred at 100°C for 4.5 hours under nitrogen.
The mixture was poured into a mixture of ethyl acetate and
25 ice water and the separated organic layer was washed with
water and brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was crystallized and the
crystal was collected by filtration and washed with hexane
and dried to give 4- ( 4-f luorophenoxy) nitrobenzene (22.96 g)
30 as a yellow crystal.
IR (KBr) : 3110, 3075, 2925, 2835, 1585, 1510 cm" -
NMR (CDCI3, 5) : 6.95-7.2 (6H, m) , 3.15-8.3 (2H, m)
APCI-MASS (m/z) : 234 (M+H+)
35
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- Ill -
To a suspension of 3-hydroxybenzyl alcohol (12 41 g)
and l-chloro-4-fluorobenzene (19.58 g) in 1 , 3-dimethyl-2-
xmidazolidinone (40 ml) were added powdered potassium
5 carbonate (8.29 g) , cuprous chloride (198 mg) and
8-hydroxyquinoline (290 mg) at room temperature, and the
mixture was stirred at 150=C for 8 hours. The mixture was
poured into a mixture of ethyl acetate and ice wate^ and
the separated organic layer was washed with water and
10 brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography
on salxca gel to give 3- ( 4 -f luorophenoxy ) benzyl alcohol
(3.98 g) as a yellow oil.
IR (Film) : 3352, 3074, 2931, 2875, 1610, 1585, 1502,
1448 cm-1
NMR (DMSO-d^r, 5) • 4 47 (7V ^ T-r: ^TT ,
6' ^1 • 'i.^/ [ZH, d, J=5.6Hz), 5.22 (IH,
t, J=5.6Hz), 6.8-7.4 (8H, m)
20
25
30
35
Preoaratinn ■)
To a solution of 4 -f luorobenzonitri le (50.0 g) and 4-
fluorophenol (50.93 g) in N, N-dimethyl f ormamide (400 ml)
was added powdered potassium carbonate (62.75 g) , and the
mixture was stirred at 150-C for 6 hours. The mixture was
cooled to 5°C and poured into ice water (2.5 t) . The
precipitates were collected by filtration, washed with
water and dried in vacuo to give 4- (4-f luorophenoxy) -
benzonitrile (87.56 g) .
IR (KBr) : 3188, 3076, 2220, 1649, 1608, 1483 cm"!
NMR (DMSO-dg, 5) : 7.05-7.15 (2H, m) , 7.2-7.45 (4H,
m), 7.8-7.9 (2H, m)
APCI-Mz^SS (m/z) : 214 (M+H+)
Preparation 1^7
To a stirred suspension of 3-acetylbenzoni tri le (25.4
g) m ethyl ether - 1,4-dioxane (10:1, 275 ml) was addid '
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bromine ( 9 ml ) dropwise at room temperature. After 4 0
minutes, to the mixture was added sodium bicarbonate (15 g)
in water (200 ml) at 0-5°C, and extracted with ethyl
acetate. The organic layer was separated and washed with
5 saturated sodium bicarbonate solution, water and brine,
dried over magnesium sulfate, evaporated in vacuo to give
3- (bromoacetyl ) benzonitrile (39.2 g) .
IR (KBr) : 3103, 3068, 2941, 2229, 1707, 1599,
1429, 1279, 1223, 1149 cm"^
10 NMR (CDCI3, 5) : 4.42 (2H, s), 7.66 (IH, dd, J=8.1,
8.IH2), 7.85-7.95 (IH, m) , 8.18-8.32 (2H, m)
Prpparation 138
A mixture of 3- (pyrazol-3-yl ) benzaldehyde (56.0 g) and
15 benzylamine (42.6 ml) in toluene (560 ml) was refluxed for
5 hours. The reaction mixture was cooled to room
temperature, and evaporated in vacuo. The residue was
suspended in ethanol (840 ml) and sodium borohydride (12.3
g) was added carefully under ice cooling. Then the mixture
20 was stirred for one hour at SOX. After additional
stirring for 2 hours at room temperature, the reaction
mixture was evaporated in vacuo. To the residue was added
water (300 ml), and extracted with dichloromethane . The
organic layer was washed with water and brine, dried over
25 magnesium sulfate, evaporated in vacuo. The residue was
chromatographed on silica gel (1.5 kg, eluring with
dichloromethane - methanol (10:1)) to give N-ben2yl-3-
(pyrazol-3-yl) benzylamine (71.8 g) .
mp : 32-83°C
30 IR (KBr) : 2290-3310 (br), 1606, 1543, 1441,
1354 cm"^
NMR (DMSO-dg, 5) : 3.71 (2H, s), 3.72 (2H, s), 6.68
(IH, d, J=2.1Hz), 7.15-7.42 (7H, m) , 7.50-7.90
(3H, m) , 12.85, 13.22 (total IK, each br)
35 APCI-MASS (m/z) : 264 (M+H"*")
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PCT/JP95/01982
10
layer
and
- 113 -
To a solution of 4- ( 4-fluorophenoxy, aniline 03
ana cycloheptanone a. 35 in ethanol (.0 .1) were^added
sxxnul.aneously a solution of sodium cyanoborohydrid^ (^4
mg) xn ethanol (30 .1, and a solution of acetic acxd (^o^
-g) xn ethanol (10 .1) over 1 hour at roo. temperature
The mxxture was srirrp>-i vr^^,^ ^-
. ^ ^ stxrrea a. room temperature for additional
-2 hours. The mixture was evaporated xn vacuo and the
resxdue was poured into a mixture of ethyl acetare and
water and adjustea to pH 8 by addition of 5N sodium
hydroxide aqueous solution. The separated organic
was washed with brxne, dried over magnesium sul^a^. ..-a
evaporated in vacuo. The residue was purif.ed ^y^olumn
chromatography on silica gel to give N-cycloheot vl-. - ( 4-
rluorophenoxy) aniline (2.11 g) as a red oil.
IR (Film) : 3405, 2925, 2855, 1735, 161C, 1495 cm-^
NMR (CDCl-., 6) • 14-2 15 n 9" . -
3' ^•'^ 2.15 (l.n, m), 3-3.5 (IH, m) ,
6-4-6.6 (2H, m), 6.75-7.05 (6H, m)
APCI-MASS (m/z) : 300 (M+H+)
Frgparatinn ]An
The mixture of 4 - ( 4 - f luorophenoxy ; benzaideh voe 73
g) a.nd benzylamine (1.29 g) was stxrred ar 120"c"fo^
nours under nitrogen. The mxxture was cooled to ^oom '
temperature and dxssolved xn ethanol (40 ml). to ^h^s
solutxon was added carefully sodxuzn oorohydrxde (303
and the mixture was stirred at room temoerature fo^
hours. The mixture was evaporated in vacuo and t^. .es^due
was extracted wxth dichloromethane . The organxc la^vi. vlas
washed with brine, dried over magnesium sulfate and' ' "
evaporated in vacuo. The resxdue was purxfxed oy^co^um^
chromatography on silica gel to gxve N-benz vl- F ( . - "
rluorophenoxy)]benzylam.xne (1.78 g) as a vel^ow ox^
IR (Film) : 3062, 3028, 2916, 2821, 1605, 1497 ^^-1
NMR (CDCI3, 5) : 3.78 (2H, s), 3.82 (2H, s), 6.9-7.:
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- 114 -
(6H, m) , 7 . 2-7 . 4 (7H, m)
APCI-MASS (m/z) : 308 (M+H"^)
Preparation 141
5 The mixture of 4- ( 4-f luorophenoxy) benzaldehyde (1.73
g) and pentylamine (1.40 g) was stirred at 120°C for 4
hours under nitrogen. The mixture was cooled to room
temperature and dissolved in ethanol (40 ml). To this
solution was added carefully sodium borohydride (303 mg) ,
10 and the mixture was stirred at room temperature for 2
hours. The mixture was evaporated in vacuo and the residue
was extracted with dichloromethane . The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
15 chromatography on silica gel to give N-pentyl-4- (4-
f luorophenoxy ) benzylamine (1.72 g) as a yellow oil.
IR (Film) : 3051, 2956, 2929, 2858, 2818, 1610,
1498 cm"^
NMR (CDCI3, 5) : 0.89 (3H, t, J=6.4Hz), 1.2-1.4 (4H,
20 m) , 1.5-1.7 (2H, m) , 2.63 (2H, t, J=7.1Hz), 3.76
(2H, s) , 6.9-7.1 (6H, m) , 7.28 (2H, d, J=9.1Hz)
APCI-MASS (m/z) : 288 (M+H"*")
Prgp&ratign 142
25 The mixture of 4- ( 4-f luorophenoxy ) benzaldehyde (2.16
g) and cyclohexylamine (1.49 g) was stirred at 120°C for 4
hours under nitrogen. The mixture was cooled to room
temperature and dissolved in ethanol (40 ml) . To this
solution was added carefully sodium borohydride (378 mg) ,
30 and the mixture was stirred at room temperature for 2
hours. The mixture was evaporated in vacuo and the residue
was extracted with dichloromethane. The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
35 chromatography on silica gel to give N-cyclohexyl-4 - { 4-
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- 115 -
fluorophenoxy)benzylamxne (3.06 g) as a yellow oil.
IR (Film) : 3034, 2929, 2852, 1608, 1^97 cm-l
NMR (CDCI3, 5) : 1.0-1.4 and 1.5-2.0 (\oH, .) ,
2.4-2.6 (IH, raK 3.78 (2H, s), 6.9-7.1 (6H,
7.28 (2H, d, J=8.4H2)
APCI-MASS (m/z) : 300 (M+H+)
g. and cyclcpentyla.ine a. 33 „ was .t.rred at Lo'c f'o" ,
hours under nitrogen. T.e .i.ture was coc.ed to roo^
temperature and dissolved in ethanol ,.o „I, . xo this
15 InrthT ""'""^ borohydride ,378 .g,
and the mixture was stirred at room temperature for 2
hours The mixture was evaporated in vacuo and the resraue
was extracted with dichXoromethane . The organic layer was
washed With brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
Chromatography on silica gel to give N-cyclopentyl .-77-
fluorophenoxyjbenzylamine ,2.67 g, as a yellow oil
IR (Film, : 3032, 2953, 2668, 2619, 1606, 1500 cm"!
«MR ,CDCl3, 5, : 1.3-2.0 ,8H, m, , 3. 05-3.25 (l.H, m,
25 ^-^-^-l '6H, m), 7.27 ,2H, d,
APCI-MASS (m/z) : 286
Prenar^iHop
30 and °* ^-'^-"uorophenoxy.benzylamine ,..35 g,
120 c for 4 hours under nitrogen. The mixture was
cooled to room temperature and dissolved in ethanol ,60
m-) . To this solution was added carefully sodium
borohydride ,757 mg, and the mixture was stirred 'at room
temperature for 2 hours. The mixture was evaporated in
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- 116 -
vacuo and the residue was extracted with dichloromethane .
The organic layer was washed with brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give N-
5 2, 3, 5, 6-tetrahydro-4H-pyran-4-yl ) -4- (4-
f luorophenoxy ) benzylamine (5.15 g) as an orange oil.
IR (Film) : 2927, 2845, 1498, 1464 cm~^
NMR (CDCI3, 5) : 1.4-1.7 (4H, m) , 3.3-4.0 (4H, m) ,
3.80 (2H, s), 6.8-7.1 {6H, m) , 7.2-7.4 (2H, m)
10 APCI-MASS (m/z) : 302 (M+H"^)
Preparation 145
The mixture of 4- ( 4-f luorophenoxy) benzaldehyde (3.24
g) and phenethylamine (2.73 g) was stirred at 120°C for 4
15 hours under nitrogen. The mixture was cooled to room
temperature and dissolved in ethanol (60 ml) . To this
solution was added carefully sodium borohydride (567 mg) ,
and the mixture was stirred at room temperature for 2
hours. The mixture was evaporated in vacuo and the residue
20 was extracted with dichloromethane. The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give N- ( 2-phenethyl ) -4 - ( 4-
f luorophenoxy) benzylamine (4.73 g) as a yellow oil.
25 IR (Film) : 3061, 3028, 2927, 2821, 1608, 1497,
1454 cm"^
NMR (CDCI3, 5) : 1.47 (IH, br s), 2.75-3.0 (4H, m) ,
3.77 (2H, s), 6.85-7.1 (6H, m) , 7.15-7.35 (7K, m)
APCI-MASS (m/z) : 322 (M+H"^)
30
Preparation 146
The mixture of 4- (4-f luorophenoxy) benzaldehyde (4.32
g) and 2-ethoxyethylamine (3.57 g) was stirred at 120°C for
4 hours under nitrogen. The mixture was cooled to room
35 temperature and dissolved in ethanol (80 ml). To this
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10
15
20
25
30
35
solution was added carefully sodium borohydride (757 mg)
and the mixture was stirred at room temperature for 2
hours. The mixture was evaporated in vacuo and the resxdue
was extracted with dichloromethane . The organic layer was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
Chromatography on silica gel to give N- (2-e thoxyethyl ) -4-
(4-fluorophenoxy)benzylamine (5.50 g) as a yellow oil
IR (Film) : 3053, 2976, 2929, 2866, 1608, 1498,
1456 cm~l
(CDCI3, 6) : 1.20 (3H, t, J=7.0Hz), 2.8-2.9 (2^
m), 3.45-3.6 (4H, m) , 3.78 (2H, s), 6.9-7.1 (6H,'
m), 7.25-7.35 {2H, m)
APCI-MASS (m/2) : 2 90 (M+H+)
Preparatinri 147
The mixture of 3- (pyra2ol-3-yl) benzaldehvde (1 27 g)
and benzylamine (I.19 g) was starred at 120»c for 4 hours
under nitrogen. The mixture was cooled to room temperature
and dxssolved in ethanol (40 ml) . To this solution was
added carefully sodium borohydride (280 mg) , and the
mxture was stirred at room temperature for 2 hours The
mixture was evaporated in vacuo and the residue was
extracted with dichloromethane. The organic laye^ was
washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by columr
Chromatography on silica gel to give N-benz vi-3- (pvrazol-3-
yl) benzylamine (1.22 g) as an oil.
IR (Film) : 3169, 3062, 3026, 2916, 2839, 1606, 1589,
1537, 1495 cm~^
NMR (DMSO-dg, 0) : 3.70 (2H, s), 3.7 (2K, s), 6.69
(IH, d, J=2.1Hz), 7.2-7.5 (7H, m) , 7.7-7.9 (3H,
s)
APCI-MASS (m/z) : 264 (M+H+)
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- 118 -
Prf^naration 148
The mixture of 3- (pyrazol-3-yl) benzaldehyde (1.72 g)
and cyclohexylamine (1.49 g) was stirred az llO'C for 4
hours under nitrogen. The mixture was cooled to room
5 temperature and dissolved in ethanol {30 ml). To this
solution was added carefully sodium borohydride (378 mg)
and the mixture was stirred at room temperature for 3
hours. The mixture was evaporated in vacuo and the residue
was extracted with dichloromethane . The organic layer was
10 washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give N-cyclohexyl-3-
(pyrazol-3-yl ) benzylamine (1.15 g) .
IR (KBr) : 3246, 3118, 3041, 2924, 2854, 1608,
15 1558 cm"^
NMR (DMSO-dg, 6) : 1.0-2.0 (lOH, m) , 2.4-2.6 (IH, m) ,
3.88 (2H, s), 6.70 (IH, br s), 7.25-7.45 (2H, m) ,
7.6-7.9 (3H, m) , 12.90 (IH, br s)
APCI-MASS (m/z) : 256 (M+H"^ )
20
Preparati on 149
The mixture of 3- (pyrazol-3-yl ) benzaldehyde (1.72 g)
and cyclopentylamine (1.70 g) was stirred at 120°C for 4
hours under nitrogen. The mixture was cooled to room
25 temperature and dissolved in ethanol (40 ml) . To this
solution was added carefully sodium borohydride (378 m.g) ,
and the mixture was stirred at room temperature for 3
hours. The mixture was evaporated in vacuo and the residue
was extracted with dichloromethane. The organic layer was
30 washed with brine, dried over magnesium sulfate and
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give N-cyclopentyl-3-
(pyrazol-3-yl) benzylamine (1.26 g) .
IR (Film) : 3265, 1610, 1589 cm"-^
35 NMR (DMSO-dg, 6) : 1.3-1.9 (8H, m) , 3.05-3.25 (IH,
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m), 3,78 (2H, s), 6.68 (IH, s), 7.2-7.4 (2H, m) ,
7.6-7.9 (3H, m) , 12.88 (IH, br)
APCI-MASS (m/2) ; 242 (M+H+)
Prepara tion 1 .SD
A mixture of 3- ( l-tritylpyrazol-3-yl ) benzaldehyde
{1.72 g) and 4-f luorobenzylamine (0.57 ml) was stirred at
120°C for 4 hours. The mixture was cooled to room
temperature and dissolved in ethanol (26 ml) . To the
mixture was added sodium borohydride (158 mg) and the
reaction mixture was stirred at 50°C for 2 hours. The
mixture was poured into water, extracted with
dichloromethane. The organic layer was washed with water
and brine, dried over magnesium sulfate, evaporated in
vacuo. The residue was chromatographed on silica gel (50
g, eluting with dichloromethane - methanol (50:1)) to give
N- (4-fluorobenzyl) -3- {l-tritylpyrazol-3-yl)benzylamine
(1.40 g) .
IR (Neat) : 3059, 2827, 1603, 1506, 1446, 1219 cm-1
20 NMR (CDCI3, 5) : 3.79 (2H, s), 3.82 (2H, s), 6.58
(IH, d, J=2.5Hz), 6.90-7.05 (2H, m) , 7.10-7.45
(20H, m) , 7.65-7.83 (2H, m)
FAB-MASS (m/z) : 524 (M+H+)
2 5 Preparat inn 151
A mixture of 3- (pyrazol-3-yl ) benzaldehyde (1.0 g) and
4-methoxybenzylamine (0.91 ml) was heated for 3 hours at
120°C. After cooling to room temperature, the mixture was
dissolved in ethanol (20 ml) . To the solution was added
sodium borohydride (220 mg) and stirred for two hours at
ambient temperature. The reaction mixture was poured into
water and extracted with dichloromethane, washed with water
and brine, dried over magnesium sulfate. The solvent was
removed in vacuo and the residue was chromatographed on
silica gel (50 g, eluting with dichloromethane - methanol
35
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(10:1)) to give N- ( 4-methoxybenzyl ) -3- (pyrazol-3-
yl) benzylamine (1.17 g) .
IR (Film) : 2370-3680 (br) , 1610, 1512, 1248,
1036 cm~l
5 NMR (CDCI3, 5) : 3.77 (2H, s), 3.79 (3H, s), 3.84
(2H, s), 6.60 (IH, d, J=2.2H2), 6.80-6.92 (2H,
m) , 7.17-7.41 (4H, m) , 7.54-7.66 (2H, m) , 7.85
{IH, s)
APCI-MASS (m/z) : 2 94 (M+H"*")
10
Preparation 152
A mixture of 3- (pyrazol-3-yl) benzaldehyde (1.0 g) and
4-f luorobenzylamine (0.8 ml) was heated for 4 hours at
120''C. After cooling to room temperature, the mixture was
15 dissolved in ethanol (20 ml). To the solution was added
sodium borohydride (220 mg) and stirred for two hours at
ambient temperature. The reaction mixture was poured into
water and extracted with dichloromethane , washed with water
and brine, dried over magnesium sulfate. The solvent was
20 removed in vacuo and the residue was chromatographed on
silica gel (50 g, eluting with dichloromethane - methanol
(10:1)) to give N- ( 4- f luorobenzyl ) -3- ( pyrazol-B-
yl ) benzylamine (1.28 g) .
IR (Film) : 2370-3680 (br) , 1605, 1508, 1220,
25 1095 cm~^
NMR (CDCI3, 6) : 3.79 (2H, s), 3.84 (2H, s), 6.61
(IH, d, J=2.3Hz), 6.90-7.10 (2K, m) , 7.18-7.45
{4H, m) , 7.52-7.70 (2H, m) , 7.75 (IH, s)
APCI-MASS (m/z) : 282 (M-i-H'^ )
30
Preparat ion 153
A mixture of 3- (pyrazol-3-yl ) benzaldehyde (1.2 g) , 4-
(dimethylamino) benzylamine-dihydrochloride (1.87 g) and
triethylamine (11.7 ml) in toluene (30 ml) was refluxed for
35 5 hours. An insoluble material was removed by filtration
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and evaporated in vacuo. The residue wa, dissolved in
ethanoi aB .i). xo the solution .as added sodiu.
borohydride ,264 and stirred for two hours at anient
temperature. .he reaction mixture was poured into ^er
and extracted with dichioromethane, washed with water aL
br.ne, dried over magnesium suifate. The solvent was
removed rn vacuo and the residue was chroma tographed on
8 1,T to'' dichloromethane -"methanol
<8 1,, t° N-(4-,dimethylamino)benzyl,-3-,pyrazol-3-
yDbenzylamine (1.68 g) .
IR -Film, : 2330-3700 ,hr,. 1614, 1524, 1446. 1350
804, 766
(CDCI3, 6) : 2.93 (6H, s), 3.75 s), 3.84
(2H, s), 6.59 (IH, d, J=2.2Hz), 6.65-6.75 (2H
7.15-7.40 (4H, 7.55-7.66 (2H, n.) , 7 76
(IH, s)
APCl-MASS ,m/z, : 440 m.Me,^.^^\^^„^
Preparation ]
3,,,,™' following compounds were obtained according to a
Similar manner to that of Preparation 57, S8, 59, 60, 62
149, 150, 151, 152 or 153.
(1) ^-Cycloheptyl-4-(4-chlorophenoxy)benzylamine
IR (Filn.) : 3035, 2925, 2855, 1610, 1590, 1505,
1485 cm~l
(CDCI3, 5) : 1..-2.0 (12H, 2.6-2.8 (IH, .)
3-76 (2H, s), 6.9-7.05 (4H, m) , 7.25-7.4 (4H ^)
APCI-MASS (m/z) : 332, 330 (M■^H+)
(2) ^^-Cycloheptyl-4-(3-fluorophe^oxy,benzylamine
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IR (Neat) : 2926, 2854, 1599, 1483, 1269, 1213 cm"^
NMR (CDCI3, 5) : 1.30-2.10 (12H, m) , 2.62-2.80 (IK,
m) , 3.77 (2H, s), 6.62-6.85 (3.H, m) , 6.93-7.05
C2H, m) , 7.18-7.40 (3K, m)
5 APCI-MASS (m/z) : 314 (M+h"^)
(3) N-Cycloheptyl-4- ( 4-trif luoromethylphenoxy) benzylamine
IR (Neat) : 2926, 2854, 1601, 1504, 1462, 1327 cirr^
NMR (CDCI3, 5) : 1.30-2.00 (12H, m) , 2.65-2.80 (IH,
10 m) , 3.78 (2H, s), 6.95-7.10 (4H, m) , 7.30-7.40
(2H, m) , 7.50-7.62 (2H, m)
APCI-MASS (m/z) : 3 64 (M+H"^ )
( 4 ) N-Cycloheptyl-4- (3, 4-methylenedioxyphenoxy ) benzylamine
15 IR (Neat) : 2924, 2854, 1606, 1502, 1481, 1354 cm" 1
NMR (CDCI3, 5) : 1.30-1.95 (12H, m) , 2.60-2.75 (IH,
m) , 3.74 (2H, s), 5.97 (2H, s), 6.47 (IH, dd,
J=8.4, 2.4Hz), 6.56 (IH, d, J=2.4Hz), 6.75 (IH,
d, J=8.4Hz), 6.85-6.96 (2K, mj , 7.20-7.31 (2H, m)
20 APCI-MASS (m/z) : 340 (M+H"^ )
(5) N-Cycloheptyl-4- (3, 5-di-tert-butyl-4-
methoxymethoxyphenoxy ) benzylamine
IR (Film) : 2920, 2860, 1587 cm"-
25 NMR (CDCI3, 5) : 1.40 and 1.42 (total i8H, s),
1.4-2.2 (14H, m) , 2.8-2.95 (IH, m) , 3.62 ana 3.54
(total 3H, s), 4.87 and 4.92 (::otal 2H, s), 6.92
(2H, s), 6.85-6.95 (2H, m.) , 7.4-7.5 (2H, m)
APCI-MASS (m/z) : 468 (M+H+)
30
(6) N-Cycloheptyl-3- ( 4-f luorophenoxy) benzylam.ine
IR (Film) : 3062, 2926, 2854, 1608, 1583, 1502,
144 6 cm~l
NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 2.6-2.3 (IH, m; ,
35 3.75 (2H, s), 6.8-7.3 (8H, m)
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- 123 -
APCI-MASS (m/z) : 314 (M+H+)
(7) ^-^y-^oheptyl-3-(i-tratylpyrazol-4-yl)benzvlanxne
NMR (OMSO-.,, 5) : ,,,,, ^, ^ -
3.70 (2H, s), 7.1-7.6 (19H, 7.76 UH
8.06 (IH, s) ' ^'
APCI-MASS (m/z) : 512 (M-H+)
IR (Neat) : 2926, 2852, 1610, 1«0, l„o 1,30
<coci3, 5, .. i.30-i..e ,i2„, 2.6;-2:ao ;:„
3.79 ,2H, s,, 3.9. ,3H. s), 7.13-v.,e ,4H '
ml, 7.63 (IH, s), 7.76 (IK, si
APCI-MASS (m/z) ; 284 (M+H+)
(9) N-CycIoheptyl-3-,l-.ethylp,.a.ol-3-yl).enzyla.,lne
IR (Neat) : 3.00 ,br), 2924. 2854. 1610, 1462. 1354
1242
««R (CDCI3, 5) : 1.30-2.00 ,12.H. 2.64-2.80 ,1K
m) , 3.83 (2H, s) 3 f -^u
^/ js.y:^ f3H, s), 6.56 (IH d
J=2.2Hz), 7.25-7.40 (3H, m) , 7.60-7 78 (2- n'
APCI-MASS (m/z) : 284 (M+H+) '
(10) ^-Cycloheptyl-3-(l-.ethylpyrazol-5-yi)i,enzvla..ne
IR (Neat) : 2924, 2854, 1608, 1462, 1 3 8 5 , ' 1 2 V5 " em" ^
NMR (CDCI3, 5) : 1 30-1 9r n 9u .
3.83 (2H, s), 3.90 (3H, s), 6.31 (^H d ^"
J=1.8Hz), 7.25-7.48 (4H, m) , 7.51 (IH d
J=1.8Hz)
30 APCI-MASS (m/z) : 284 (M+H+)
(11) N-Cycloheptyl-3-(iznidazol-4-yl)benzylamire
IR (Film) : 2300-3600 (br) , 2924, 2854, I6IO,
14 60 cm~l
-NMR ,D„SO-d„ 5) : 1.20-1.95 ,12H, 2.55-2.75 .IH.
35
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m) , 3.73 (2K, s), 7.05-7.80 ( 6H, m) , 12.00-12.25
(IH, br)
APCI-MASS (m/z) : 270 {M+H"^)
5 (12) N-Cycloheptyl-4- ( 5-methyl-l, 3, 4-oxadia2ol-3-
yl) benzylamine
IR (KBr) : 3442, 3292, 3211, 2920, 2852, 1689, 1576,
1502, 1450 cm"-
NMR (CDCI3, 6) : 1.30-2.40 (12H, m) , 2.61 (3H, s),
10 2.63-2.80 (IH, m) , 3.87 (2H, s), 7.45-7.54 (2H,
m) , 7.93-8.05 (2H, iti)
APCI-MASS (m/z) : 286 (M+H"^ )
(13) N-Cycloheptyl-4- ( 4-benzyl-5-methyl-4H-l , 2, 4-triazol-3-
15 yl ) benzylamine
IR (Neat) : 3298, 2924, 2852, 1612, 1527, 1458,
13 58 cm~^
NMR (CDCI3, 5) : 1.30-1.93 (12H, m) , 2.38 (3H, s),
2.60-2.77 (IH, m) , 3.81 (2H, s), 5.16 (2K, s),
20 6.90-7.05 (2H, m) , 7.27-7.55 (7H, m)
APCI-MASS (m/z) : 375 (M+H"*" )
(14) N-Cycloheptyl-3- ( 2 -methyl -2H-tetrazo 1-5- yl ) benzylamine
IR (Neat) : 2924, 2854, 1520, 1462, 1365 cm"-
25 NMR (CDCI3, 6) : 1.30-1.98 {12H, m) , 2.65-2.80 (IH,
m) , 3.86 {2H, s), 4.40 (3H, s), 7.40-7.48 (2H,
m) , 7.95-8.05 (IH, m) , 8.09 (IH, s)
APCI-MASS (m/z) : 286 (M+H"^)
30 (15) N-Cycloheptyl-3- ( l-methyl-lH-tetrazol-5-yl ) benzylamine
IR (Neat) : 2924, 2854, 1533, 1452, 1292 cm"l
NMR (CDCI3, 5) : 1.30-1.98 (12H, m) , 2.65-2.80 (IH,
m) , 3.88 (2H, s), 4.18 (3H, s), 7.46-7.65 (3H,
m) , 7.75 (IH, s)
35 APCI-MASS (m/z) : 286 (M+H"^)
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5
10
15
20
25
30
16) "-Cycloheptyl-4-,lH-l,2,4-trxazoi-l-yl,benzviamne
mp : 53-54°C
IH (KBr) : 3101, 2922, 2852, 1518, 1460, 1277, .1.7
984 cm~^
(CDCI3, 5) : 1.30-2.00 (12H, , 2.60-2.80 nH
3.84 (2H, s), 7.40-7.55 (2K, m) , 7.55-7.7 '
{2H, m) , 8.10 (l.u, s), 8.54 {IH, si
APCI-MASS (m/z) : 271 (M^H+)
(17) N-CycloheDtyl-4- MH-I ? t_i-v;=^ 1
- y- ^ ^.2, 3-tria2ol-l-yl)benzvlan-.ine
: 7 8-79°c
IH (KBr, .. 3319. 3124, 2920. 2652,' 1520. 1230. no,
1041 cm"l
(CDCI3, 5) : 1.30-2.00 (12H, , 2.63-2.80 (IH
3.87 (2H, s), 7.45-7.57 (2H, n.) , 7.64-7.75'
(2H, m), 7.85 (IH, s), 7. 93 (IH, s)
APCI-MASS (m/z) : 2 71 (M^.H+)
(IB) N-Cycloheptyl-4-(2.H-l,2,3-triazol-2-yl)benzylan.ine
IP. (Neat) : 2926, 2854, 1608, 1514, 146G, 1412, 1381
1259, 951, 824 cm-l
NMR (DMSO-d„ 6) : 1.20-1.90 (12H, .) , 2. 50-. 70 (IP
3.74 (2H, s), 7.45-7.55 (2H, xn) , 7.90-8.00
(2H, m) , 8.10 (2H, s)
APCI-MASS (m/z) : 271 (M+K+)
(19) N-Cycloheptyl-(4-methylpxperazan-l-yl)benzvlai-nxne
IR (Film) : 2925, 2850, 2795, 1615, 1515 ct"!
NMR (DMSO-dg, 6) : l. 3-1.9 (12H, m) , 2.21 (3H, s)
2.4-2.5 (4H, m), 3.1-3.2 (4K, m) , 3.2-3. 4S (1h
6.85 (2H, d, J=8.5Hz), 7.15 (2H, d, J=3 5H-
APCI-MASS (m/z) : 3 02 (M+H"^)
N-Cycloheptyl-4- ( 4 -methylsul fonylammophenvl ) -
35 benzylamine
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IR (KBr) : 3020, 2930, 2855, 1605, 1495 cm" ^
NMR (DMSO-dg, 5) : 1.3-2.0 {12H, m) , 2.5-2.7 (IH, m) ,
3.01 (3H, s), 3.72 (2H, s), 7.27 (2H, d,
J=8.5Hz), 7.39 {2H, d, J=8.5Hz), 7.57 (2H, d,
5 J=8.2Hz), 7.63 (2H, d, J=8.2Hz)
APCI-MASS (m/z) : 373 {M+H"^)
(21 ) N-Cycloheptyl-4- (N-benzoylsulf amoyl) benzylamine
IR (KBr) : 3477, 3057, 2927, 2858, 1599, 1545 cm"l
10 NMR (DMSO-dg, 5) : 1.3-2.2 (12H, m) , 3.1-3.3 (IH, m) ,
4.17 (2H, s), 7.2-7.45 (5H, m) , 7.4-7.5 (2H, m) ,
7.75-7.9 (2H, m) , 8.4-8.7 (IH, br)
APCI-MASS (m/z) : 387 (M+H"^)
15 (22) N-Cycloheptyl-4- (N-phenylsulf onylcarbamoyl ) benzylamine
IR (KBr) : 3091, 2929, 2858, 1647, 1601, 1537 cm"^
NMR (DMSO-dg, 6) : 1.35-2.2 (12H, m) , 3.1-3.3 (IK,
m) , 4.11 (2H, s), 7.35-7.5 (5H, m) , 7.8-7.9 (2H,
m) , 7.93 (2H, d, J=B.lHz)
20 APCI-MASS (m/z) : 387 (M+H"^ )
( 23 ) N-Cycloheptyl-4- ( 3-pyridylmethyl ) benzylamine
IR (Film) : 3304, 3026, 2924, 2852, 1574, 1512 cm" ^
NMR {CDCI3, 6) : 1.4-2.2 (12H, m) , 2.6-2.8 (IK, m) ,
25 3.75 (2H, s), 3.95 (2H, s), 7.1-7.5 {6H, mj , 8.45
(IH, dd, J=4.8, 1.8Hz), 8.49 (IH, d, J=1.8Hz)
APCI-MASS (m/z) : 295 (M+H"^ )
(24 ) N-Cycloheptyl-4- ( 4-pyridylmethyl ) benzylamine
30 IR (Film) : 3323, 3022, 2924, 2852, 1599 cm~^
NMR (CDCI3, 5) : 1.3-2.1 (12H, m) , 2.6-2.8 (IK, m) ,
3.77 (2H, s), 3.94 (2H, s), 7.09 (IH, dd, J=4.5,
1.6Hz), 7.12 (2H, d, J=9.4Hz), 7.29 (IK, d,
J=9.4Hz), 8.48 (2H, dd, J=4.5, 1.6Hz)
35 APCI-MASS (m/z) : 295 (M+H"*")
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35
- 127 -
(25, N-Cycloheptyl-.- (pyrazol-l-yl„ethyl,benzylan,.„e
IR (Neat, : 2924, 2854. 1514, 1458. 1090. 750 cm"!
NMR ,CDCl3. 5, : 1 .30-1.98 ,12H. „, , 2.56-2.7V UH
3.76 ,2H. s,, 5.30 ,2H. s,. 6.27 <1„, dd, '
J-2.0HZ,, 7.10-7.40 (5H, m) , 7.54 (IH, d
J-2.0H2,
APCI-MASS (m/z) : 284 (M+H+,
10 ^"^^''"'"^'^^-^-'^""^'^-"l-^-Vi-thyl.benzylaMine
IR (Neat, : 3280 ,br, , 2924, 2854, 1506, 1458, 1230
1107, 1076
NMR (CDCl^, 6) : 1 20-1 m ^ ^
^-^^ ^-^^ ^12H, m) , 2.60-2.78 (IH
3.76 (2H, s), 5.10 (2H, s), 6.90 (IH, s)
7.00-7.40 (5H, m), 7.54 (IH, s)
APCI-MASS (m/z) : 284 (M+H+)
(27) N-Cycloheptyl- (6-hydroxy-2, 5, 7, 8-tetra.ethvlchron.an-2-
yi) methylamine
NMR (DMSO-d„ 5) : 1.17 (3H, s), I.3-I.9 (4H, .)
1-97 (3H, 3), 2.01 (3H, s), 2.04 (3H, s), 2.5-. 7
(3H, m) , 7.39 (IH, s)
APCI-MASS (m/z) : 332 {M+H+)
(28) N-Cycloheptyl-4- [N- (3, 5-di-tert-butyl-4-
hydroxyphenyl ) carbamoyl ] benzylamine
■ IH (KBr) : 3639, 3304, 2926, 2858, 1643, 1606, 1547 cm"!
NMR (DMSO-d„ 6, : 1.3-1.9 (12H, m) , I.39 (ISH, s)
2.5-2.7 (IH, m), 3.77 (2H, s), 6.78 (IH, s), 7 45
(2H, d, J=8.2Hz), 7.88 (2K, d, J=8.2H2), 7.58
(2H, s), 9.87 (IH, s)
APCI-MASS (m/z) : 451 (M+H+)
(29) N-CycIoheptyl-4-rN-(4-fluorophenyl) carbamoyl J-
benzylamine
IR (KBr) : 3354, 2927, 2854, 1651, 1612, 1529,
20
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1512 cm~l
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.5-2.65 (IH,
m) , 3.77 (2H, s), 7.1-7.3 (2H, m) , 7.75-7.85
(2H, m) , 7.47 {2H, d, J=8.2H2), 7.89 (2H, d,
5 J=8.2Hz), 10.22 (IH, s)
APCI-MASS (m/z) : 341 (M+H"^)
( 30 ) N-Cycloheptyl-4- [N- ( 4 - f luorophenyl ) -N-
methylcarbamoyl ] benzylamine
10 IR (KBr) : 3475, 3187, 3120, 3024, 292", 2853, 1643,
1597, 1541, 1500 cm" ^
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.4-2.6 (IH, m)
3.33 (3H, s), 3.60 (2H, s), 7.05-7.3 (8H, m)
APCI-MASS (m/z) : 355 (M-rH"^)
15
( 31 ) N-Cycloheptyl-4- ( tert-bucyldimethylsilyloxymerhyl ) -
benzylamine
IR (Film) : 2927, 2850, 1514, 1464 cm"^
NMR (DMSO-dg, 6) : 0.08 (6H, s), 0.89 (9H, s), 1.3-
20 1.9 (12K, m), 2.5-2.65 (IK, m) , 5.67 (2H, s),
4.67 (2H, s), 7.22 (2H, d, J=8.3Kz), 7.28 (2K, d
J=8 . 3Hz)
APCI-MASS (m/z) : 348 (M+H"^)
25 (32) N-Benzyl-3-phenoxybenzylamine
IR (Film) : 3062, 3030, 2829, 1583, 1487, 1452 cm"^
NMR (DMSO-dg, 5) : 2.63 (IH, br s), 3.64 (2K, s),
3.66 (2H, s), 6.8-7.45 (14H, m)
APCI-MASS (m/z) : 290 (M+H"^)
30
(33) N-Benzyl-3- { 4-fluorophenoxy) benzylamine
IR (Film) : 3062, 3030, 2916, 2829, 1608, 1584,
1500, 1450 cm"^
NMR (CDCI3, O) : 3.78 (2H, s), 3.79 (2K, s), 6.8-7.4
35 (13H, m)
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■ 15
- 129 -
APCI-MASS (m/z) : 308 (M+H+)
(3.) N-Benzyl-3-(i-Methylpyrazol-3-yl)benzylaxn.ne
IR .Neat) : 3313, 3028, 2935, 1608, 1498, 1452 13
1242 cm-l
NHR (CDCI3, 5) : 3.83 (2H, s), 3.85 (2H, s), 3 9^
(3H, s), 6.55 (IH, d, J=2.3Hz), 7.18-7.42 (8H
m), 7.64-7.73 (IH, m) , 7.77(1H, s)
APCI-MASS (m/z) : 278 {M+H+)
(35) N-Benzyl-3-(l-n.ethylpyrazol-5-yl)benzylairine
IR (Neat) : 3310, 3026, 2830, 1606, 1454, 1387
1275 cm-1
NMR (CDCI3, 6) : 3.84 (2H, s), 3.87 (2H, s), 3.89
(3H, s), 6.31 (IH, d, J=1.9Hz), 7.20-7.45 (9H
^) r 7.51 (IH, d, J=1.9Hz)
APCI-MASS (m/z) : 278 (M+H+)
20 ^^-"^^^^^--^-^^--thylpy.azol-3-yl)benzylamine
IR (Neat) : 3310, 3028, 2937, 2820, 1504, 1454,
1430 cm"^
NMR (CDCI3, 6) : 3.81 (2H, s), 3.83 (2H, s), 3 95
(3H, s), 6.53 (IH, d, J=2.3Hz), 7.18-7.43 ( 8H
m), 7.70-7.80 (2H, m)
APCI-MASS (m/z) : 278 (M+H")
(37) N-Benzyl-4-(l-n^ethylpyrazol-5-yl)benzvlamine
IR (Neat) : 3305, 3026, 2820, 1493, 1454, 1385
1275 cm-1
NMR (CDCI3, 5) : 3.85 (2H, s), 3.87 (2H, s), 3.89
(3H, s), 6.30 (IH, d, J=1.9Kz), 7.20-7.50 ( 9h
m) , 7.51 (IH, d, j=i.9Hz)
APCI-MASS (m/z) : 278 (M+H+)
35 (38) N-Benzyl-4-(pyrazol-3-yl)benzylamxne
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IR (Neat) : 2250-3680 (br) , 1514, 1495, 1454, 1350 cm"
NMR (DMSO-dg, 5) : 3.69 (4H, s), 6.67 (IH, d,
J=2.1Hz), 7.15-7.50 (7H, m) , 7.60-7.90 (3H, m) ,
12.81, 13.20 (total IH, each br)
APCI-MASS (m/z) : 264 (M+H"^)
(39) N-Benzyl-4- ( l-methylpyrazol-4-yl ) benzylamine
mp : 90-91°C
IR (KBr) : 3300, 3020, 2914, 2854, 1570, 1473, 1452,
10 1194, 1097 cm"^
NMR (CDCI3, 5) : 3.81 {2H, s), 3-82 (2H, s), 3.94
(3H, s), 7.20-7.50 (9H, m) , 7.60 (IH, s), 7.75
(IH, s)
15
APCI-MASS (m/z) : 278 (M+H"^)
(40) N-Benzyl-3- ( imidazol-4-yl ) benzylamine
IR (Neat) : 2200-3560 (br) , 1608, 1491, 1454 cm~^
NMR (DMSO-dg, 5) : 3.72 (4H, s), 7.10-7.40 (7H, m) ,
7.41-7.80 (4H, m)
20 APCI-MASS (m/z) : 264 (M+H"^)
(41) N-Ben2yl-3- ( 2-methyl-2H-tetrazol-5-yl) benzylamine
IR (Neat) : 3028, 2825, 1520, 1452, 1363, 804 cm'^
NMR (CDCI3, 5) : 3.84 (2H, s), 3.89 (2H, s), 4.40
25 (3H, s), 7.20-7.52 (7H, m) , 7.96-8.07 (IK, m) ,
8.12 (IH, s)
APCI-MASS (m/z) : 280 (M+H"^)
( 42 ) N-Benzyl-3- ( l-methylpyrazol-4-yl ) benzylamine
30 IR (Neat) : 3305, 3028, 2935, 2827, 1610, 1450, 1363,
1230 cm"l
NMR (CDCI3, 6) : 3.84 (4H, s), 3.94 (3H, s), 7.13-
7.40 (8H, m) , 7.45 (IH, s), 7.62 (IH, s), 7.77
(IH, s)
35 APCI-MASS (m/z) : 278 (M+H+)
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(^3) N-(4-Methoxybenzyl)-4-(4-fluorophenoxy)benzyla..ine
IR (Neat) : 3001, 2903, 2833, 1610, 1500,' 1460, 1248,
NMR (CDCl-5, 5) • 1 7S r9K -r ^
3' °> ■ -i./S (2h, s), 3.76 (2H, s), 3.80
(3H, £), 6.82-7.10 (8H, .-n) , 7.20-7.35 ^4-
APCI-MASS (m/z) 339 (M+H+)
Prensr;:^ r i nn I
The following compound was obtained accord':ng eo a
similar manner to that of Preparation 31, 38, 39 or 89.
4- (l-Tritylpyrazol-4-yl) to"!uer^°
NMR (DMSO-d„ 6) : 2:27 (Jh,":,, 7.1-7.5 (19H, m) ,
7.73 (IH, £), 8.04 (IH, s)
Preparation
The following compounds were obtained according to a
similar manner to that of Preparation 28.
(1) 4-(l-Tritylpyrazol-4-yl)benzyl bromide
NI^R (DMSO-dg, 6) : 4.70 a.nd 4.77 (total 2K, s),
7.0-7.8 (21H, m)
(2) 3-3enzoylbenzyl bromide
IR (Film) : 3059, 3028, 1686, 1599 cm"!
NMR (CDCI3, 5) : 4.53 (2K, s), 7.35-7.9 (9K,
APCI-MASS (m/2) : 277, 275 (M+.H^j
Preoar^ rinn 157
The following compounds were obtained according to a
similar manner to that of Preparation 63.
(1) N-Cycloheptyl-4- ( l-tritylpyrazol-4-yl ) benzvlamxne
IR (Film) : 3057, 3028, 2918, 2852, 1641, 1605,
1566 cm~-
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NMR (DMSO-dg, 6) : 1.3-2.0 (12H, m) , 2.55-2.75 (IK,
m) , 3.68 and 3.75 (total 2H, s), 7.05-7.25 (5H,
m) , 7 . 3-8 . 1 (16H, m)
APCI-MASS (m/z) : 512 (M+H")
5
(2) N-Cycloheptyl-4- ( 2-cyanophenyl ) benzylamine
IR (Film) : 3060, 3030, 2910, 2855, 2225, 1597,
14 80 cm"^
NMR (CDCI3, 5) : 1.4-2.0 {12H, m) , 2.65-2.85 (IH, m) ,
10 3.85 (2H, s), 7.4-7.8 (BH, m)
APCI-MASS (m/z) : 305 (M+H"^)
(3) N-Cycloheptyl-4- [2- ( l-trityl-lH-tetrazol-5-
yl ) phenyl ] benzylamine
15 IR (KBr) : 3058, 3026, 2924, 2854, 1603, 1493,
14 4 6 cm" •'■
NMR (DMSO-dg, 5) : 1.3-1.9 (12H, m) , 2.6-2.75 (IH,
m) , 3.68 (2H, s), 6.8-6.95 (5H, m) , 7.01 (2H, d,
J=7.9Hz), 7.20 (2K, d, J=7.9Hz), 7.3-7.8 (14K, it
2 0 FAB-MASS (m/z) : 590 (M+K"*")
(4 ) N-Cycloheptyl-3-benzoylbenzylamine
IR (Film) : 3059, 2927, 2855, 1653, 1599, 1580 crc"-
NMR (CDCI3, 5) : 1.3-2.0 (12H, m) , 2.6-2.8 (IH, m) ,
25 3.85 (2H, s), 7.3-7.8 (9H, m]
APCI-MASS (m/z) : 308 (M+H"^)
Preparation 158
The following compounds were obtained according to a
30 similar manner to that of Preparation 50 or 51.
(1) 3- { l-Methylpyrazol-3-yl ) benzaldehyde
IR (Neat) : 2941, 2829, 2730, 1695, 1606, 1585, 1439,
1242 cm"^
35 NMR (CDCI3, 5) : 3.98 (3H, s), 6.62 (IH, d, J=2.2Hz),
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7.42 (IH, d, J=2.2Hz), 7.51-7.62 (IH, lu) , 7.77-
7-86 (IH, m), 8.05-8.13 (IH, m) , 8.25-8.32 (IH,
m) , 10.07 (IH, s)
APCI-MASS (m/z) : 187 (M+K+)
(2 ) 3- ( l-Methylpyrazol-5-yl ) benzaldehyde
mp : 72-74°C
IR (KBr) : 3041, 2831, 2733, 1697, 1579, 1462, 1377 cm"
NMR (CDCI3, 6) : 3.94 (3H, s), 6.39 (IH, d, J=1.4Hz),
7.56 (IH, d, J=1.4Hz), 7.58-7.74 {2H, m) , 7.89-
7.97 (2H, m) , 10.09 (IH, s)
APCI-MASS (m/z) : 187 (M+H+)
(3) 4- (Pyrazol-l-yl) benzaldehyde
mp : 53-55-0
IR (KBr) : 3109, 2833, 2744, 1693, 1608, 1394, 1213,
760 cm~l
NMR (CDCI3, 6) : 5.43 (2H, s), 6.34 (IH, dd, J=2 . 1 ,
2.1Hz), 7.25-7.35 (2H, m) , 7.45 (IK, d, J=2.1Hz),
7.59 (IH, d, J=2.1Hz), 7.80-7.90 (2H, m) , 9 99
(IH, s)
APCI-MASS (m/z) : 187 (M+H+)
(4) 4- (Imidazol-l-ylmethyl)benzaldehyde
^^^^t) : 2600-3600 (br), 1695, 1506, 1232, 1076,
818, 737 cm"l
NMR (CDCI3, 5) : 5.22 (2H, s), 6.85-7. 95 (7H, m) ,
10.01 (IH, s)
APCI-MASS (m/z) : 187 (M+H+)
15
20
30
Prepar;:i tion 1 59
The following compound was obtained according to a
similar manner to that of Preparation 47.
35
3- (Imidazol-4-yl) benzaldehyde
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mp : 135-138°C
IR (KBr) : 2080-3390 (br) , 1691, 1606, 1479, 1327,
1186, 1066, 978, 781 cm"^
NMR (DMSO-dg, 5) : 7.59 (IH, dd, J=7.6, 7.6Hz), 7.67-
5 7.80 (3H, m) , 8.05-8.15 (IH, m) , 8.31 (IH, s),
10.04 (IH, s), 12.30 (IH, br)
APCI-MASS (m/z) : 173 (M+H"^)
Preparation 160
10 The following compounds were obtained according to a
similar manner to that of Preparation 44, 45, 84, 110, 124
or 126.
(1 ) 4- ( 5-Methyl-l, 3, 4 -oxadiazol-2-yl ) benz aldehyde
15 IR (KBr) : 2829, 1701, 1610, 1590, 1550, 1421 cm"
NMR (CDCI3, 6) : 2.66 (3H, s), 7.96-8.07 (2H, m) ,
8.15-8.26 (2H, m) , 10.10 (IH, s)
APCI-MASS (m/z) : 189 (M+H"^)
20 (2) 4- ( 4-Benzyl-5-methyl-4H-l, 2, 4-triazol-3-
yl ) benzaldehyde
IR (KBr) : 3450 (br), 1689, 1608, 1572, 1531,
1207 cm"l
NMR (CDCI3, 5) : 2.44 (3H, s), 5.22 (2H, s), 6.93-
25 7.07 (2H, m) , 7.30-7.47 {3H, m) , 7.70-7.80 (2H,
m) , 7.90-8.00 (2H, m) , 10.05 (IH, s)
APCI-MASS (m/z) : 278 (M+H+)
Preparation 161
30 The following compound was obtained according to a
similar manner to that of Preparation 97.
4 -Benzyl -2- ( 4-hydroxymethyl ) phenyl-5-methyl-4H-l , 2,4-
triazole
35 mp : 118-121°C
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15
- 135 -
IR (KBr, : 2600-3650 ,br,. 1535, 1,87, 1,25, 1363,
1039, 854, 739 cm~^
^CDCl3, 5, : 2.3e (3H, s), 3.10-3.25 (IH, ,
4-65-4.77 (2H, m), 5.14 (2H, s), 6.90-7.03 (2F
m), 7.25-7.50 (7H, m)
APCI-MASS (m/z) : 280 (M+H*)
Preparation i (^r>
The following compound was obtained according to a
similar manner to that of Preparation 31.
N-Methyl-N-methoxy-4-r4-{methvlsin^^., i
benzamide ^^^thylsulfonylamxno) phenyl ] -
IR (KBr) : 3210, 2935, 1630, 1608, 1525 cm"!
NMR (DMSO-d^-, 5) • ^ n^i ^-^u
6' O) . 3.04 (3ri, s), 3.28 f3H, s), 3 58
s), 7.32 (2H, d, J=8.6Hz), 7.6-7.8 (6H, m)
9.91 (IH, s) '
Preoara tinn ] f^-^
The following compounds were obtained according to a
similar manner to that of Preparation 36.
(1) ^-('^-MethylsulfonylaminophenyDbenzaldehyde
23 ^^^"^ ■ ''''' 2995, 2840, 2745, 1695, 1600, 1525
1500 cm-1
NMR (DMSO-dg, 6) : 3.06 (3H, s), 7.33 (2H, d,
J=8.5Hz), 7.78 (2H, d, J=8.5Hz), 7.89 (2H, d
J-8.2HZ), 7.98 (2H, d, J=8.2Hz), 9.98 (r-", br s)
10.04 (IH, s)
30 APCI-MASS (m/z) : 276 (M+H+)
(2) 4- (N-Benzoylsulfamoyl)benzaldehyde
IR (KBr) : 3381, 3057, 2883, 1697, 1599, 1560 cm"!
NMR (DMSO-d(-, 6) : 7 3-7 S f3H -70^
35 6' ^ • /.3 /.5 (3H, m, , 7.9-8.0 (2H, m) ,
7.44 (2H, d, J=8.3Hz), 8.00 (2H, d, J=8.3Hz),
20
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10,03 (IH, s)
APCI-MASS (m/z) : 290 (M+H"*")
Preparation 164
5 The following compounds were obtained according to a
similar manner to that of Preparation 33 or 34.
(1) 4- (N-Methyl-N-methoxysulfamoyl) benzamide
IR (KBr) : 3292, 3201, 3111, 2979, 2943, 1605, 1562,
10 1504 cm"-
NMR (DMSO-dg, 6) : 3.28 (3H, s), 3.54 (3H, s), 7.49
(2H, br s) , 7.74 (2H, d, J=8.4Hz), 7.88 (2H, d,
J=8 . 4Hz)
APCI-MASS (m/z) : 245 (M+H"^)
15
(2) N-Methyl-N-methoxy-6-hydroxy-2, 5, 7, 8-
tetramethylchroman-2-carboxamide
IR (KBr) : 3479, 2983, 2935, 2870, 1655 cm" ^
NMR (DMSO-dg, 6) : 1.4 9 (3H, s), 1.97 (3H, s), 2.0 5
20 (6H, s), 1.6-1.75 (IH, m) , 2.4-2.6 (3H, m) , 3.34
(3H, 3), 3.57 (3H, s), 7.48 (IH, s)
APCI-MASS (m/z) : 294 (M+H"^ )
Preparati on 165
25 The following compound was obtained according to a
similar manner to that of Preparation 105.
4- (N-Phenylsulf onylcarbamoyl ) benzaldehyde
IR (KBr) : 3185, 3155, 3105, 2935, 2850, 1740, 1695,
30 1645, 1605, 1565, 1550 cm~ -
NMR (DMSO-dg, 6) : 5.95 {2H, d, J=7.5Hz), 7.35-7.45
(2H, m) , 7.75-7.9 (3H, m) , 8.20 (2H, d, J=7.5Hz),
10.02 (IH, s)
APCI-MASS (m/z) : 290 (M+H"^)
35
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15
20
25
- 137 -
The following compound was obtained according to a
similar manner to that of Preparation 66.
N-Cycloheptyl-3-benzylbenzylamine
IR (Film) : 3059, 3026, 2926, 2852, 1601, 1495 cm"!
NMR (CDCl^, 6) • 1 3-2 0 nPH ^ o
3' 1.3 2.0 (12H, m), 2.6-2.8 (IH, m) ,
^-^^ s), 7.0-7.5 (9H, m)
APCI-MASS (m/z) : 294 (M+H+)
Prpnar-atinn 1^7
_ The following compound was obtained according to a
similar manner to that of Preparation 36.
2-Formyl-6-hydroxy-2, 5, 7, 8-tetramethylchromane
IR (KBr) : 3541, 2981, 2933, 2872, 2833, 2727
1732 cm-1
NMR (DMSO-d„ 5) : 1.66 C3H, s), 1.7-1.9 (IH, m) ,
2. 2-2.es (3H, m), 1.97 (3H, s), 2.07 (3H, s)
2-08 {3H, s), 7.55 (IH, s), 9.53 (l.H, s)
APCI-MASS (m/2) : 244 (M+H+)
Preparation i ^«
TO a solution of 2-chloro-6-methyl-4-n.ethylthio-3-
nxtropyridine (13.25 g) .n methanol (150 ml) was added 28^
sodium methoxide in methanol (23.4 ml), and the mixture was
refluxed for 7 hours under nitrogen. The mixture was
cooled and the precipitates were collected by filtration
washed With methanol and diisopropyl ether and dried undl^
Phosphorus pentoxide to give 2-methoxv-6-methyl-4-
n.ethylthio-3-nitropyridine (10.29 g) as a yellow powde^
IR (KBr) : 3024, 2997, 2951, 2924, 2856, 1587, i;41
1495, 1452
NMR (DMSO-dg, 5) : 2.46 (3H, s], 2.57 OH, s),
3.94 (3H, s), 7.07 (IH, s )"
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APCI-MASS (m/z) : 215 (M+H"^)
Prpparation 169
To a solution of 2, 4-dichloro-6-methyl-3-nitropyridine
5 (41.40 g) in methanol (400 ml) was added dropwise a 28":
solution of sodium methoxide in methanol (38.6 ml), and the
mixture was stirred at 60''C for an hour under nitrogen.
The mixture was evaporated in vacuo and the residue was
extracted with ethyl acetate. The organic layer was washed
10 with brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography
on silica gel to give 2-chloro-4-methoxy-6-methyl-3-
nitropyridine (30.43 g) as a pale yellow crystal.
IR (KBr) : 3088, 2987, 2953, 2883, 1601, 1552, 1524,
15 14 71 cm"
NMR (DMSO-dg, 6) : 2.51 (3H, s), 4.01 (3H, s),
7.42 (IH, s)
Preparation 170
20 To a solution of 2-chloro-4-methoxy-6-methyl-3-
nitropyridine (30.42 g) in methanol (300 ml) was added
dropwise a solution of sodium methanethiolate (12.63 g) in
methanol (200 ml) at room temperature and the mixture was
stirred at 50°C for 4 hours under nitrogen. The mixture
25 was evaporated in vacuo and the residue was extracted with
ethyl acetate. The organic layer was washed with brine,
dried over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
to give 4-methoxy-2-methylthio-6-methyl-3-nitropyridine
30 (30.23 g) as a yellow powder.
IR (KBr) : 3066, 2997, 2956, 2933, 2858, 1585, 1549,
1514, 1466 cm"^
NMR (DMSO-dg, 5) : 2.51 (3H, s), 2.53 (3H, s),
3.95 (3H, s), 7.11 (IH, s)
35 APCI-MASS (m/z) : 215 (M+H"^)
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35
- 139 -
Prep^r;:^ti nn 17]
To a suspension of 4-inethoxy-2-methvlthio-6-n.e-hvl-3-
n.tropy..d.ne (30.15 ,) ethanol (300 .1, adde^.'conc
for 10 hours. The mixture was cooled to 5'c and the
precipitates were collected by filtratxon, washed with
ethanol and dixsopropyl ether, and dried in vacuo unde^
Phosphorus pentoxide to give 4-hydroxy-2-methylthio-6- '
-ethyl-3-nitropyridine (19.79 g) as a yellow oowder
'^^^^ = 2989, 2920, 2783, 1551, 1518 cm"!
NMR (DMSO-dg, 5) : 2.39 (3H, s), 2.50 (3H, s),
6.62 (IH, s)
P^g"^^^ri on 17p
To a suspension of ^-hydroxy-2-methylthio-6-methyl-3-
nxtropyridane (30.65 g) in phosphorus oxychloride (140 8 g)
was stirred at lOO^c for 10 hours. The mixture was pou'reo
xnto a mxxture of ethyl acetate and water, and neutralized
,0 - f °' hydroxide aqueous solution. The
insoluble materials were filtered off, and the filtrate was
separated. The organic layer was washed w.th br.ne, dr.e^
over magnesium sulfate and evaporated in vacuo The
residue was purifxed by column chromatography on sxl.ca gel
to g.ve 4-chloro-2-methylthio-6-methyl-3-nitroovridine
(-Ll.87 g) as a yellow powder.
IR (KBr) : 3103, 3053, 2933, 1560, 1518 cm"!
NMR (DMSO-dg, 6) : 2.55 (3K, s), 2.59 (3.H, s),
7-55 (IH, s)
APCI-MASS (m/z) : 221, 219 (M+H^)
TO a solutxon of 2 , 4-d< chloro- 6-MethyI-3-ni t ropyridine
K-.H g) m 1,4-dioxane (50 ml) and methanol (50 ml) was
added Raney Nickel ,NDT-90, purchased from Kawaken Fire
Chemicals) ,ca. 2 g) , and the mixture was hydrogenated for
25
30
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4 hours under atmospheric pressure. Raney Nickel was
filtered off and washed with methanol, and the filtrate was
evaporated in vacuo. The residue was purified by column
chromatography on silica gel to give 3-amino-2 , 4-dichloro-
5 6-methylpyridine (3.53 g) as a yellow oil.
IR (Film) : 3479, 3385, 3221, 3188, 2924, 1616, 1576,
1543, 1471 ciii~-
NMR (DMSO-dg, 6) : 2.28 (3H, s), 5.52 (2H, br s),
7.23 (IH, s)
10 APCI-MASS (m/z) : 181, 179, 177 (M+H^)
Preparation 174
To a solution of 3-amino-2 , 4-dichloro-6-methylpyridine
(3.51 g) in dichloromethane (50 ml) was added N,N-
15 dimethylaniline (2.88 g) at 5°C, followed by dropwise
addition of phenyl chlorof ormare (3.41 g) , and the mixture
was stirred at room temperature for 3.5 hours. The mixture
was washed with dilute hydrochloric acid and brine, dried
over magnesium sulfate and evaporated in vacuo. The
2C residue was crystallized from diisopropyl ether and the
crystal was collected by filtration, washed with
diisopropyl ether and dried in vacuo to give 2 , 4 -di chloro-
6-methyl-3-phenoxycarbonylaminopyridine (1.96 g).
IR (KBr) : 3282, 3244, 3184, 3013, 1718, 1637, 1608,
25 1524, 1491 cm~^
NMR (DMSO-dg, 6) : 2.27 (3K, s), 7.1-7.5 (5H, m) ,
7.65 (IH, s), 10.10 (IH, br s)
APCI-MASS (m/z) : 301, 299, 297 (M+H+)
3 0 Preparat ion 175
A mixture of 3- (pyrazol-3-yl ) benzaldehyde (1.0 g) and
2-methoxybenzylamine (0.91 ml) was heated for 4 hours at
120°C. After cooling ro room temperature, the mixture was
dissolved in ethanol (20 ml) . To the solution was added
35 sodium borohydride (220 mg) and stirred for two hours at
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ambxent temperature. The reaction mixture was ooured . nto
water and extracted wxth d.chloromethane, washed with water
and brine, dried over magnesium sulfate. The solvent was
removed in vacuo and the residue was chromatographed on
sxlaca gel (50 g, eluting with dichloromethane - methanol
(10:1)) to give N- (2-methoxybenzyl ) -3- (pyrazol-3-
yl) benzylamine (1.06 g) .
IR (Film) : 2400-3600 (br) , 1603, 1493, 1462,
1244 cm"i
NMR (CDCI3, 5) : 3.81 (3H, s), 3.84 (2K, s), 3 35
(2H, s), 6.59 (IH, d, J=2.2Hz), 6.80-6.98
m), 7.17-7.50 (4H, m), 7.53-7.67 (2H, m) , 7 79
(IH, s)
APCI-MASS (m/z) : 294 (M+H^)
Prenar arion M f,
Am.ixture of 3- (pyrazol-3-yl ) benzaldehvde (1.0 g) and
3-metnoxybenzylamine (0.91 m.l) was heated for 4 hours a-
120=C. After cooling to room temperature, the mixture Jas
dissolved in ethanol (20 ml). To the solution was added
sodium borohydride (220 mg) , and stirred for two ho^^^-^
ambient temperature. The reaction mixture was ooured irto
water and extracted with dichloromethane, washed with wate^
and brine, dried over magnesium sulfate. The solven^ wa.
removed in vacuo and the residue was chromatoarapred on
silica gel (50 g, elutmg with dichloromethane - methane^
^15:1); to give N- ( 3-methoxybenzyl ) -3- (pyrazol-3-
yl ) benzylamine (1.24 g) .
IR (Neat) : 2370-3680 (br) , 1603, 1487, 1439, 1263,
1157, 1045 cm~l
NMR (CDCI3, 5) : 3.80 (3H, s), 3.81 (2H, s), 3.95
(2H, s), 6.61 (IH, d, J=2.2Hz), 6.75-6.85 JlH,
m), 6.86-6.97 (2H, m) , 7.19-7.43 ( 3H, m) , 7 5S-
7.68 (2H, m), 7.76 (IK, s)
APCI-MASS (m/z) : 2 94 (M+H"^)
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Preparat ion 177
A mixture of 4- ( 4-f luorcphencxy ) benzaldehyde (1.5 g)
and a-phenylpropyiamine (1.15 tt.I) was heated for 4 hours at
120°C. After cooling to room temperature, the mixture was
5 dissolved in ethanol (30 ml) . To the solution was added
sodium borohydride (2 62 mg) and stirred for two hours at
airJDient temperature. The reaction mixture was poured into
water and extracted with dichloromethane, washed with water
and brine, dried over magnesium sulfate. The solvent was
10 removed in vacuo and the residue was chromatographed on
silica gel (50 g, eluting with dichloromethane - methanol
(15:1)) to give N- ( 3-phenylpropyl ) -4- ( 4- f luorophenoxy ) -
benzylamine (1.92 g) .
IR (Neat) : 3028, 2929, 2855, 2818, 1606, 1497, 1454,
15 1250, 1211 cm"^
NMR (CDCI3, 5) : 1.85 (2H, qn, J=7.4Kz), 2.55-2.75
(4H, m) , 3.75 (2H, s), 6.83-7.10 (6H, m) , 7.10-
7.36 (7H, m)
APCI-M.ASS (m/z) : 33 6 (M+K"")
20
Prpnaration 178
A mixture of 3- (pyrazol-3-yl ) benzaldehyde (1.0 c, and
phenethylamine (0.875 ml) was heated for 4 hours at 120°C.
After cooling to room, temperature, the mixture v;as
25 dissolved in ethanol (20 ml ) . To the solution was added
sodium borohydride (220 mg) and stirred for two hours at
ambient temperature. The reaction mixture was poured into
v/ater and extracted with dichloromethane, washed with wate
and brine, dried over magnesium sulfate. The solvent was
30 removed in vacuo and the residue was chromatographed on
silica gel (50 g, eluting with dichloromethane - methanol
(15:1 to 10:1)) to give N- ( 2-phenylethyl ) -3- (pyrazol-3-
yl ) benzylam.ine (1.27 g) .
IR (Neat) : 2300-3700 (br) , 1606, 1495, 1452, 1354,
35 1097 cm"-
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NMR (CDCI3, 6) : 2.76-3.00 n.) , 3.86 (2H, s)
6.59 (IH, d, J=2.2HZ), 7.10-7.43 (7H, ra) , 7.53-
7.68 (2H, m), 7.86 (IH, s)
APCI-MASS (m/z) : 278 {M+H+)
A mixture of ( 4-f luorophenoxy) benzaldehyde (1 5 g)
and (S)-l-phenylethylamine (1.08 xnl) was heated for 4 hours
at 120»C. After cooling to room temperature, the mixture
was dissolved xn ethanol (30 ml). To the solutio.n was
added sodium borohydride (262 mg) and stirred for two hours
at ambient temperature. The reaction mixture was ooured
.nto water and extracted with dichloromethane, washed with
water and brine, dried over magnesium sulfate. The solvent
was removed .n vacuo and the residue was chromatographed on
silxca gel (50 g, eluting with n-hexane - ethvl acetate
(4:1 to 2:1) to give N- [ (S) -1-phenylethyl] -4- (4-
fiuorophenoxy)benzylamine (2.23 g) .
^^^^-t) : 3028, 2966, 2831, 1606, 1498, 1452, 1250
1213 cm"^
K^R (CDCI3, 5) : 1.38 (3H, d, J=6.6Hz), 3.56 (IH, d,
J-13.1HZ), 3.63 (IH, d, J=13.1Hz), 3.82 (IH q
J=6.6Hz), 6.83-7.12 ( 6H, m) , 7.15-7.43 (7H,'m)'
APCI-MASS (m/z) : 322 (M+H+)
f^^D^ = -31.2° (C=1.05, CHCI3)
Pren^r;:;l--i r^n ^ on
A mixture of 4- ( 4 -f luorophenoxy ) benzaldehyde (1 5 g,
(R)-I-Phenylethylamine (1.08 ml) was .heated for 4 hours
at 120'>C. After cooling to room temperature, the mixture
was dissolved in ethanol (30 ml). To the solution was
added sodium borohydride (262 mg) and stirred for two hou--
at ambient temperature. The reaction mixture was poured
xnto water and extracted with dichloromethane, washed wi t^
water and brine, dried over magnesium sulfate. T.he solve-
35
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was removed in vacuo and the residue was chromatographed o
silica gel (50 g, eluting with n-hexane - ethyl acetate
(4:1 to 2:1) to give N- [ (R) -1-phenylethyl ] -4- ( 4-
f luorophenoxy ) benzylamine (2.12 g) .
5 IR (Neat) : 3028, 2966, 2831, 1606, 1498, 1452, 1250
1213 cm"^
NMR (CDCI3, 5) : 1.37 (3H, d, J=6.6Hz), 3.56 (lH,d,
J=13.1Hz), 3.63 (IH, d, J=13.1Hz), 3.81 (IH, q,
J=6.6Hz), 6.83-7.12 (6H, m) , 7.15-7.42 (7H, m)
10 APCI-MASS (m/z) : 322 (M+H"^)
[a]g° : +31.7° (C=1.02, CHCI3)
Preparation 181
The following compounds were obtained according to a
15 similar manner to that of Preparation 71, 78 or 173.
( 1 ) 3-Amino-2-methoxy-6-methyl-6-methylthiopyridine
IR (Film) : 3444, 3352, 2984, 2947, 2922, 2860, 1585
1559, 1462 cm"l
20 NMR (DMSO-dg, 5) : 2.26 (3K, s), 2.43 (3H, s), 3.84
(3K, s), 4.39 (2H, br s), 6.64 (IH, s)
APCI-MASS (m/z) : 185 (M+H"^)
( 2 ) 3-Amino-4-chloro-2-methylthio-6-methylpyridine
25 IR (KBr) : 3417, 3300, 3207, 2922, 1618, 1558 cm~-
NMR (DMSO-dg, 5) : 2.31 (3H, s), 2.51 (3K, s), 4.96
(2H, br s) , 6.96 (IK, s)
APCI-MASS (m/z) : 191, 189 (M+H^)
30 Preparat ion 182
The following compounds were obtained according to a
similar manner to that of Preparation 74 or 79.
( 1 ) 2-Methoxy-6-methyl-4-methylthio-3-
35 phenoxycarbonylaminopyridine
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IR (KBD : 3217, 17.0, 1700, 16«, 1541, 1518 crr,"-
NMR ,D„SO-d„ 5, . 2.3. ,3H, s,, 2.4 5 ,3H, s,, 3.86
<3H. 6.81 ,1H, s), 7.0-7.5 , 5K, n, , 8.76 ard
9-17 (total IK, br s)
APCI-MASS (m/z) : 305 (M+H"")
(2) 4-Chloro-2-methylthio-6-inethyl-3-
phenoxycarbonyliminopyridine
IR (KBr, : 3207, 3026, 3001, 2926, 1724, 1597, 1554,
1524, 1489 cm~^
NMR (DMSO-d„ 6) : 2.48 (3H, s), 2.51 (3H, s), 7 0-
7.5 (6H, m), 9.37 and 9.77 (total IH, br s)
APCI-MASS (m/2) .- 3II, 309 (M+H^)
Preparation -[fi^
The following compound was obtained according to a
similar manner to that of Example 7, 8, 9, 10, 13, 14 15
16 or 17. ' '
1-14- (4-Fluorophenoxy)benzyl ] -3- [2, 4-bis (methvi tMo) -
c-methylpyridin-3-yl ] urea
IR (KBr) : 3305, 3107, 2924, 1633, 1574, 1498 ci.-l
NMR (DMSO-d„ 5) : 2.39 (6H, s), 2.44 (3H, s),
(2H, d, J=5.8Hz), 6.53-6.7 (IH, br) , 6.86 (IH,
s), 6.9-7.4 (8H, m) , 7.54 (IK, br s)
APCI-MASS (m/2) : 444 (M+K^)
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F.x ample 1
To a solution of N- ( 4-biphenylylmethyl ) - '
cycloheptylamine (559 mg) in dichloromethane (10 ml) was
added 2 , 4 , 6- trimethylphenyl isocyanate (322 mg) , and the
5 mixture was stirred at room temperature for 1.3 hours under
nitrogen. The mixture was evaporated in vacuo and the
crystalline compound was collected by filtration using
hexane:ethyl acetate (5:1) to give 1- ( 4-biphenylylmethyl ) -
l-cycloheptyl-3- (2, 4, 6-trimethylphenyl) urea (710 mg) .
10 IR (KBr) : 3320, 2920, 2855, 1625, 1505 cm"^
NMR (DMSO-dg, 6) : 1.5-1.8 (12H, m) , 2.00 (6H, s),
2.20 (3H, s), 4.4-4.55 (IH, m) , 4.55 (2H, s),
5.48 (IH, s), 6.79 (2H, s), 7.3-7.65 (9H, m)
APCI-MASfe (m/z) : 441 (M+H"^ )
15
Example 2
To a solution of N- ( 4-biphenylylmethyl ) -
cycloheptylamine (559 mg) in dichloromethane (10 ml) was
added 2, 6-diisopropylphenylisocyanate (406 mg) , and the
20 mixture was stirred at room temperature for 1.1 hours. The
mixture was evaporated in vacuo and the residue was
purified by column chromatography on silica gel to give
1- {4-biphenylylmethyl ) -l-cycloheptyl-3- (2,6-
diisopropylphenyl ) urea (885 mg) as a crystal.
25 IR (KBr) : 3415, 3340, 3060, 3030, 2960, 2930,
2865, 1625, 1500 cm"^
NMR (CDCI3, 5) : 0.9-1.3 (lOH, m) , 1.5-1.8 (12H,
m) , 1.95-2.1 (2H, m) , 2.8-3.0 (2H, m) , 4.4-4.6
(IK, m) , 4.56 (2H, s), 5.47 (IH, s), 7.0-7.65
30 (12H, m)
APCI-MASS (m/z) : 48 3 (M-rH'^j
35
Example 3
To a solution of 2-amino-4 , 6-dimethoxypyrimidine (465
mg) and triphosgene (297 mg) in 1 , 2-dichloroethane (20 ml)
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was added triethylamine (304 mg) and fh. •
refluxed for 1.8 hours Th. .
temperature and a so w ■ ^° —
3 added thereto. ...er bein.' s .'reraT::^"^^^^ ^
3- wrs, the was^ouredtt :: :/:r:r^-
separated orasn-fr^ i »^ater and the
ea organic layer was washed with brin^ w • .
magnesium sulfate ;,nH -^-^-^e, dried over
^^rate ano evaporated in vacuo rh^
purified by column chromatograoh v on silL T
(^-bxphenylyl.ethyl)-,_.,.,,,,,,;,_3_;;^^^^^ ' ' ^^^^
dimethoxypyri:nidin-2-yl)urea (205 mg) '
IR (KBr) : 3390, 3225, 2925 2855
168;), 1600,
1525 cm-1
NMR (CDCI3, 5) : 1 4-2 1 MPH ,
... ^- - -^.1 (12H, m) , 3.86 (6H s)
APCI-MASS (m/z) : 46I (m+H^)
-Examplo /]
To a solution of 2 4
triphosgene (297 :na, ■ w '"'^^^°^°-^^l-ne (441 n.g) ana
^ (^y/ mg) an dichloromethare M- -
^riethylan,ine ,30. 5-c and tl ""''"^
for 2 hours under nUrogen The ! """" """^^^
added. The mixtnr« "^ometnane (3 ml) was
^our. and e.a^Lv:: ti^' .tr.rr"""
b.phenylyl„ethyl,-i-cy,i„h^p,yj_3_^^ 4 6-
trimethylphenyljurea 1752 mg)
(KBr, . 3265, 2860, 1^35, 1520 ..-1
<CDCl3, 6, : a..5-2.Z5 ,12H, , , 3-". „ -
7.3-7. 65 (9H, m) ' '
APCI-MASS (m/z) : 453
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Example 5
The following compounds were obtained according to
similar manners to those of Examples 1, 2, 3 and 4.
5 (1) 1-Cycloheptyl-l- (4-phenoxyphenylmethyl) -3- (2, 6-
diisopropylphenyl ) urea
IR (KBr) : 3415, 3360, 2960, 2925, 2865, 1645,
1590 cm"^
NMR (CDCI3, 5) : 0.9-1.35 (12K, m) , 1.4-2.1 {12H,
10 m) , 2.8-3.0 (2H, m) , 4.35-4.5 (IH, m) , 4.50 {2H,
s), 5.46 (IK, s), 6.95-7.45 (12H, m)
APCI-MASS (m/z) : 499 (M+H"^)
(2) 1- (3-Biphenylylmethyl) -l-cycloheptyl-3- (2,4,6-
■15 trimethylphenyl ) urea
IR (KBr) : 3325, 2925, 2855, 1625, 1505 cm"^
NMR (CDCI3, 5) : 1.4-2.1 (12H, m) , 1.97 {6H, s),
2.20 (3H, 5), 4.2-4.4 (IH, m) , 4.57 (2H, s), 5.49
(IH, s), 6.78 (2H, s), 7.3-7.7 (9H, m)
2 0 APCI-MASS (m/z) : 441 (M+H"^)
(3) 1- (2-Biphenylylmethyl ) -l-cycloheptyl-3- (2,4,6-
trimethylphenyl ) urea
IR (KBr) : 3285, 2970, 2930, 2860, 1635, 1520 cm"
25 NMR (CDCI3, 6) : 1.4-2.0 (12H, m) , 1.96 (6H, s),
2.21 (3H, s), 4.25-4.4 (IH, m) , 4.37 (2H, s),
5.30 (IH, s), 6.80 (2H, s), 7.2-7.7 (9H, m)
APCI-MASS (m/z) : 441 (M+H"*")
30 (4) 1-Cycloheptyl-l- (4-phenoxyphenylmethyl) -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3295, 2920, 2855, 1620, 1590, 1510,
1490 cm"-'-
NMR (CDCI3, 5) : 1.4-1.8 (12H, m) , 2.00 (6H, s),
35 2.22 (3H, s), 4.35-4.5 (IH, m) , 4.48 (2H, s),
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30
35
5-47 (IH, s), 6.81 (2H, s), 7.0-7.4 (9H, n»
APCI-MASS (m/z) : 457 (M+H+)
(5) 1-Cycloheptyl-l- ( 3-phenoxyphenylinethyl ) -3- (2,4,6-
trimethylphenyl) urea
IR (KBr) : 3310, 2925, 2855, 1625, 1605, 1585,
1510 cm-^
NMR (CDCln, 5) • I 4-1 p ■ .
' -^-^ a2H, m) , 2.00 (6H, s),
2-21 {3H, s), 4.25-4.45 (IH, m) , 4.47 (2H, s)
^■-54 (IH, s), 6.80 (2H, s), 6.85-7.4 (9F,
APCI-MASS (m/z) : 4 57 (M+H+)
(6) l-Cycloheptyl-l-r4-(pyridin-2-yl)benzylJ-3-(2,4,6-
trimethylphenyl) urea
^^^^^ ^ 3410, 3320, 2920, 2855, 1625, 1585,
1560, 1505 cra~^
NMR (CDCI3, 6) : 1.4-1.8 (12H, , 2.03 (6H, s)
2-20 (3H, s), 4.3-4.5 (IK, m) , 4.58 (2H, s), 5 .9
(IH, s), 6.80 (2H, s), 7.2-7.3 (IH, m) , 7.51 (.p
J=8.3Hz), 7.7-7.85 (2H, m) , 8.02 (2H, d
J=8.3H2), 8.7-8.75 (IH, m)
APCI-MASS (m/z) : 442 (M+H+)
(7) 1-Cycloheptyl-l- [4- (pyridin-3-yl) benzyl ] -3- (2,4,6-
trimethylphenyl) urea
IR (KBr) : 3315, 2920, 2855, 1645, 15^0 cm"!
NMR (CDCI3, 6) : 1.4-1.9 (12H, m) , 2.02 (6H, s),
2-21 (3K, s), 4.35-4.5 (lH,m), 4.58 (2H, s)' 5 4
(IH, s), 6.80 (2H, s), 7.39 (IK, dd, J=7 9'
4.9KZ), 7.3-7.7 (4H, m) , 7.86 (IH, dt, J=8'2
1-8HZ), 8.60 (IH, d, j=3.6Hz),
8.83 (IH, s)
APCI-MASS (m/z) : 442 (M+H+)
(8) 1-Cycloheptyl-l- [ [2- (4-chlorophe.nyl) thiazol-4-
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yl ] methyl ] -3- (2 , 4 , 6-trimethylphenyl ) urea
IR (KBr) : 3300, 2920, 2855, 1645, 1610,' 1495 cm~^
NMR (CDCI3, 6) : 1.5-2.0 (12H, m) , 2.13 (6H, s),
2.24 (3H, s), 4.2-4.4 (IH, m) , 4.61 (2H, s), 6.85
5 (2H, s), 7.18 (IH, s), 7.24 (IH, s),
7.35-7.45 (2H, m) , 7.8-7.9 (2K, m)
APCI-MASS (m/z) : 483 (M+H"*")
( 9) 1-Cycloheptyl-l- [ (2-phenyliniidazol-5-yl ) methyl ] -3-
(2, 4, 6-trimethylphenyl) urea
IR (KBr) : 3100, 2925, 2855, 1620, 1570 cm~^
NMR (DMSO-dg, 5) : 1.35-1.8 (12K, m) , 2.06 (6H, s),
2.21 (3H, s), 4.05-4.2 (IK, m) , 4.36 (2H, s),
6.83 {2H, s), 7.23 (IH, s), 7.3-7.5 (3H, m) , 7.8-
7.9 (2H, m) , 8.68 (IH, s), 12.55 (IH, s)
APCI-MASS (m/z) : 431 (M+H"^)
(10) 1-Cycloheptyl-l- [4- (pyrrol- 1 -yl ) benzyl ] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3310, 2920, 2855, 1625, ■ 1525, 1510 cm"^
NMR (CDCI3, 5) : 1.4-2.05 (12H, m) , 2.01 (6H, s),
2.21 (3H, s), 4.3-4.5 (IH, m) , 4.53 (2H, sj, 5.46
(IH, s) , 6.3-6.4 (2H, m) , 6.80 (2H, s), 7.05-7.15
(2H, m) , 7 . 35-7 . 5 (4H, m)
APCI-MASS (m/z) : 430 (M+H+ )
(11) 1-Cycloheptyl-l- [3- (pyrrol-l-yl ) benzyl] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3320, 2920, 2855, 1625, 1610, 1505 cm~'
30 NMR (CDCI3, 5) : 1.45-2.05 ;i2H, m) , 2.01 f6H, s),
2.21 (3H, s), 4.3-4.5 (IK, m) , 4.56 (2H, s), 5.47
(IH, s), 6.35-6.4 (2H, m) , 6.80 (2H, s), 7.05-
7.10 (2H, m) , 7.25-7.5 (4H, m)
APCI-MASS (m/z) : 430 (M+H"^ )
10
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25
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.12) ^-^J-i°heptyl-l-„,-,p,„„,.,.^„p^^^^^^_^_^^^^^^^_^^^
4' 6-trimethylphenyl) urea
IH (KBr; : 3220, 2920, 16.5, 1605, 1575, 1500 cxn'^
NHR (DMSO-d„ 5) : l.,-,.e U2H, , ,.,3 3;
2-21 (3H, s), 4.1-4.3 (IH, m) , 4.56 (2H, s)
6-35-6.4 (2K, m), 6.84 (2H, 3), 6.5-6.55 (2F rr)
6.55-6.65 (2H, n.) , 8.50 (IH, br s), 8.51 (IH,' d '
J=5.6H2) '
APCI-MASS (m/z) : 431
30
35
(13:
l-Cycloheptyl-l-f(6-phenylpyridin-3-yl):nethylJ-3-
(2, 4, e-trimethylphenyl) urea
IR (KBr) : 3315, 2920, 2855, 1630, 1560, 15^5 en"!
^^°"'3^ 5) : 1.4-2.05 (12H, . 2. 09 (6H, 3)",
^-^-^-3 (IH, m), 4.60 (2H, s), 5.53
(IH, s), 6.83 (2H, s), 7.35-7. 55 (3H, n.) , 7 7-7 9
(2K, xn), 7.95-8.05 (2H, m) , 8.70 (IH, s)
APCI-MASS (m/z) : 442 (.M^H+)
(14) ^-Cy^^°heptyl-l-p-(2-methylthiazol.-4-yl)benzvl]-3-
(2, 4, 6-trimethylphenyl) urea
(KEr) : 3360, 2925, 2855, 1620, 1505 cm''-
NMR (CDCI3, 6) : I. ,-2. 05 (12H, , i . 93 (6H, s)
2.20 (3H, 3), 2.78 (3K, 3), 4.4-4.55 (IH, :n) '
4.57 (2H, 3), 5.49 (IH, s), 6.78 (9^ s) 7
(IH, S), 7.35-7.5 (2H, m) , 7.79 (IH, d, J^l'^n^,
7.93 (IK, s) ~
APCI-MASS (m/z) : 4 62 (.M+H^)
(15) 1-Cycloheptyl-l- r3-(pyrazol-3-yl) benzyl] -3- (2,4,6-
trimethylphenyl) urea
IR (KBr) : 3405, 3210, 2925, 2855, 1640, 1610,
1500 cm~I
NMR (CDCl-,, o) : 14-iq 1 1 ojj n n r.
^ • ^ • ^ (i2H, m) , 2.08 (6H, 3),
2.20 (3H, s), 4.1-4.25 (IH, m) , 4.54 (2H, s )' ,
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6.63 (IH, s), 6.82 (2H, s), 7.2-7.8 (6H, m) ,
12.86 (IH, s)
APCI-MASS (m/z) : 431 (M+H"^)
5 (16) 1-Benzyl-l- (4-phenoxybenzyl) -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3310, 3030, 2915, 1630, 1590, 1505 cm"
NMR (CDCI3, 5) : 2.01 (6H, s), 2.22 (3H, s), 4.63
(2H, s), 5.64 (IK, s), 6.82 (2H, s), 7.0-7.4
10 (14H, irj
APCI-MASS (m/z) : 4 51 (M+H"^)
(17) 1-Furfuryl-l- (4-phenoxybenzyl) -3- (2, 4, 6-
trimethylphenyl ) urea
15 IR (KBr) : 3280, 3030, 2975, 2915, 1625, 1595,
1530, 1505 cm~^
NMR (CDCI3, 5) : 2.10 (6H, s), 2.25 (3K, s), 4.55
(2H, s), 4.61 (2H, s), 6.03 (IH, s), 6.25-6.3
(IH, m) , 6.35-6.4 (IH, m) , 6.86 (2H, s), 6.95-
20 7.45 (lOH, m)
APCI-MASS (m/z) : 441 (M+H"*")
(18) 1-Cycloheptyl-l- [4- (4-chlorophenyl ) benzyl ] -3- (2, 4, 6
trimethylphenyl ) urea
25 IR (KBr) : 3400, 3300, 2925, 2855, 1655, 1625,
1505 cm"^
NMR (CDCI3, 5) : 1.5-2.05 (12H, m) , 2.01 (6H, s),
2.21 (3H, s) , 4.3-4.5 ( IH, m) , 4.55 (2H, s), 5
(IH, s), 6.80 (2H, s), 7.4-7.65 (8H, m)
30 APCI-MASS (m/z) : 476 (M+H"^)
(19) 1-Cycloheptyl-l- [4- ( 4- f luorophenyl ) benzyl j -3- (2, 4 , 6
rrimethylphenyl ) urea
IR (KBr) : 3400, 3300, 2925, 2855, 1655, 1625,
35 1490 cm~^
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- 153 -
NMR {CDC1-. 6) • 1 5-2 1=; n9u
3, ^' -=^-1- (x2H, IP.), 2.01 (6H, s)
2-21 {3H, s), 4.4-4.6 (IH, m) , 4.55 (^-H, s) '5
(IH, s), 6.80 (2K, s;, 7.05-7.2 (2.H, m) , 7 I.-
(6H, m)
APCI-MASS (in/2) : 459 (M+H")
(20) l-Cycloheptyl-l-[4-(4-broir.ophenyl)benzyl]-3-(2,4,6-
trimethylphenyl ) urea
IR (KBr) : 3400, 3300, 2920, 2855, 1655, 1625,
1505 cm"!
(CDCI3, 5) : 1.5-2.05 (12H, , 2.01 (6H, s)
2-21 (3H, s), 4.35-4.55 (2H, s), 5.46 (IH, s),
6-80 (2H, s), 7.45-7.6 (8H, m)
APCI-MASS (m/z) : 521 (M+H+)
(21) i-Cycloheptyl-l-[4-(4-methylphenyl)benzyl]-3-(2,4,6-
trimethylphenyl ) urea
IR (KBr) : 340O, 3310, 3020, 2920, 2855, 1660,
1625, 1500 cm~l
(CDCI3, 6, : 1.4-2.1 (12H, .), 1.99 (6H, s),
2.20 (3K, s), 2.40 (3H, s), 4.35-4 . 55 (^K r^)
^^-54 (2H, s), 5.48 (l.H, s), 6.79 (2H, 3), 7
(2H, d, J=7.9.Hz), 7.4-7.5 (4H, m) , 7.59 (2H d
J=8.3Hz) ' '
25 APCI-MASS (m/z) : 455 (.M+.H+)
(22) l-Cycloheptyl-l-r4-(4-dimethylaminophenyl,benzyl]-3-
(2, 4, 6-trimethylphenyl) urea
IR (KBr) : 3405, 3325, 2920, 2855, 2805, 1650,
1610, 1535, 1500 cm-I
NMR (CDCI3, 5) : 1.5-2.2 (12H, m) , 1.98 ( 6H, s>
2.20 (3H, s), 3.00 (6H, s), 4.4-4.6 (IH, m) ' 4 5.
(2H, s), 5.50 (IH, s), 7.4-7.65 (8K, .m)
APCI-MASS (m/z) : 4 84 (M+H+ )
20
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(2 3) 1-Cycloheptyl-l- [4- ( 4-bromophenoxy ) benzyl] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3410, 3325, 2920, 2855, 1635, 1585,
1505 cm"-^
5 NMR (CDCI3, 6) : 1.5-2.1 (12H, m) , 2.01 (6H, s),
2.22 (3H, s), 4.35-4.55 (IH, m) , 4.49 (2H, s),
5.46 (IH, s), 6.81 (2H, s), 6.85-7.05 (4H, m) ,
7.3-7.5 (4H, m)
APCI-MASS (m/z) : 537 (M+H"^)
10
(24) 1-Cycloheptyl-l- ( 4-benzoylbenzyl ) -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3325, 2920, 2855, 1655, 1605, 1505 cm~^
NMR (CDCI3, 5) : 1.4-2.05 (12H, m) , 2.06 (6H, s),
15 2.22 (3H, s), 4.2-4.4 (IK, m) , 4.61 {2H, s), 5.45
(IH, s), 6.82 (2H, S), 7.5-7.7 (5H, Iti) , 7.75-7.9
(4H, m)
APCI-MASS (m/z) : 469 (M+H"^)
20 (25) 1-Cycloheptyl-l- (4-benzylbenzyl) -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3305, 3025, 2920, 2855, 1625, 1505 crr."-
NMR (CDCI3, 5) : 1.5-2.05 (12H, m) , 1.93 (6H, s),
2.21 (3H, s), 3.97 (2H, s), 4.35-4.55 (IH, m) ,
25 4.46 (2H, s), 5.42 (IH, s), 6.78 {2K, s), 7.1-7
(9H, m)
APCI-MASS (m/z) : 455 (M+H"^)
(26) 1-Cycloheptyl-l- ( 4 -phenyl thiobenzyl ) -3- (2, 4, 6-
30 trimethylphenyl ) urea
IR (KBr) : 3315, 2920, 1630, 1610, 1505 cm"-
NMR (CDCI3, 5) : 1.4-2.05 (12H, m) , 2.00 (6K, s),
2.22 (3H, s), 4.3-4.5 (IH, m) , 4.4B (2H, s), 5.^
(IH, s), 6.81 (2H, s), 7.07 (IH, t, J=8.6Hz),
35 7.25-7.45 (8H, m)
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APCI-MASS (m/z) : 413 (M+H+)
(27) l-Cycloheptyl-i-M6-phenylth.opyridxn-3-yl)n.ethyiJ-3-
(2,4, 6-trimethylphenvl) urea
^ IR (KBr) : 3310, 2925, 2855, 1630, 1585, 1510 cm"!
NMR (CDCI3, 5) : 1.5-2.05 (12H, , 2.05 (6H, s)
2-23 (3H, s), 4.05-4.2 (IH, m) , 4.47 (2H, s)
5-49 (IK, s), 6.84 (2H, s), 6.90 (IK, d, '
(6H, m), 8.43 (IK,' d' J=1.8Hz)
10 APCI-M.ZISS (m/z) : 474 (M-fH-)
(28) 1-Cycloheptyl-l- {4-benzoylaminobenzyl) -3- (2,4, 6-
trimethylphenyl) urea
IR (KBr) : 3350, 3055, 2920, 2855, 1655, 1610,
1550 cm-l
NMR (DMSO-d„ 5) : I.4-I.9 (12K, .) , 2. 06 (6H, s)
2-15 (3K, s), 4.1-4.3 (IK, m) , 4. 51 (2H, s), 6.81
(2H, s), 7.05 (IH, d, J=7.7H2), 7.29 (IH, d
J=V.7Kz), 7.40 (IK, s), 7.5-7.7 (4K, n.) , 1.1,
(IH, s), 7.9-8.0 (2K, m) , 10.26 (iH, s)
APCI-MASS (m/z) : 484 (M+K^)
15
20
(29) 1-Cycloheptyl-l- [4- (phenylcarbamoyl)benzyl) -3- (2,4,6-
triraethylphenyl ) urea
^""^^^ = 3425, 3300, 2920, 2860, 1670, 1635,
1600, 1540 cm"l
NMR (DMSO-dg, 5) : I.4-I.9 (12K, m) , 2.11 {6H, s)
2-21 (3H, 3), 4.1-4.3 (IK, m), 4.58 (2H, s) / l 85
(2H, s), 7.13 (IK, t, J=7.3Kz), 7.3-7.5 (4K, n)
7.65 (IK, 3), 7.77 (2K, d, J=7.6Kz), 7.93 (2K d
J=8.2H2), 10.17 (IH, s) ' '
APCI-MASS (m/z) : 484 {M+H+)
30
35
(30) l-Cycloheptyl-l-(4- (2-pyridylcarbainoyl) benzyl] -3-
(2,4, 6-trimethylphenyl) urea
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IR (KBr) : 3335, 292C, 2855, 1675, 1635, 1610,
1580, 1525, 1505 cm~^
NMR (DMSO-dg, 6) : 1.4-1.9 (12H, m) , 2.10 (6H, s),
2.21 (3H, si, 4.1-4.3 (IH, m) , 4.57 (2H, s), 6.84
5 (2H, s), 7.16 (IH, dd, J=6.8, 5.8H2), 7.42 (2H,
d, J=8.2Hz), 7.63 (IH, br s), 7.8-7.9 (IH, m) ,
8.00 {2.H, d, J=8.2Hz), 8.19 (IH, d, J=8.4Hz),
8.35-8 .45 (IH, m) , 10.71 (IK, s)
APCI-MASS (m/z) : 485 (M+H"^)
10
(31) 1-Cycloheptyl-l- [4- ( 4- f luorophenoxy ) benzyl] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3305, 2920, 2855, 1630, 1500 cm"^
NMR (CDCI3, 5) : 1.5-2.1 {12H, m) , 2.00 (6H, s),
15 2.22 (3H, s), 4.3-4.5 (IK, m) , 4.76 (2H, s), 5.47
(IH, s), 6.82 (2H, s), 6.9-7.1 (6H,.rr.), 7.36 (2K,
d, J=8.5Hz)
APCI-MASS (m/z) : 475 (M+H"^)
20 (32) 1-Cycloheptyl-l- [4- (phenylsul famoyl ) benzyl ] -3- (2, 4, 6-
t rimethylphenyl ) urea
IR (KBr) : 3395, 313C, 2925, 2860, 1635, 1600,
150 0 cin"l
NMR (DMSO-dg, 6) : 1.3-1.8 (12K, rr.) , 2.01 (6H, s),
25 2.20 (3H, s), 4.05-4.25 (IH, m) , 4.50 (2H, s),
6.81 (2H, s), 7.0-7.15 (3K, m) , 7.15-7.3 (2K, m) ,
7.42 (2H, d, J=8.3Hz), 7.57 (IH, br si, 7.70 (2K,
d, J=8.3Hz) , 10.23 (IH, s)
APCI-MASS (m/z) : 520 (M+H"^)
30
( 33 ) 1-Cycloheptyl-l - [ 4- (phenylsul fonyl amino) be.nzyl ] -3-
(2,4, 6- t rimethylphenyl) urea
IR (KBr) : 3410, 3110, 2925, 2860, 1630, 1510 cm" ^
NMR (DMSO-dg, 5) : 1.3-1.8 (12H, m) , 1.99 (6H, s),
35 2.20 (3H, s), 4.0-4.2 (IH, m) , 4.37 (2H, s), 6.81
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15
20
25
(34)
- 157 -
s), 7.01 (2H, d, J=8.3Hz), 7.15 (2H, d
J=8.3Hz), 7.37 (IH, br s), 7 . 5-7 . 65 '( 3H, , 7.7-
7-8 (2H, m) , 10.22 (IH, br s)
APCI-MASS (m/z) : 520 (M+H+)
1-Cycloheptyl-l- [4- ( 3-thienyl ) benzyl ] -3- (2,4, 6-
trlmethylphenyl) urea
IR (KBr) : 3320, 2920, 1624, 1504, 1252, 775 0^'^
NMR (CDCl-,, 5) • 1 40-9 in < i ou
3' ^> i.^u ^.10 (12H, m) , 2.00 (6H, s)
2.20 (3K, s), 4.35-4.55 (IH, ^) , 4.53 (2H, s) '
5-47 (IH, s), 6.79 (2H, s), 7.34-7.50 (5H, m) ,
7.55-7.66 (2H, m)
APCI-MASS (m/z) : 447 (M+H+)
(35) 1-Cycloheptyl-l- [4- (2-thienyl) benzyl] -3- (2,4,6-
trimethylphenyl ) urea
IR (KBr) : 3319, 2922, 1624, 1504, 1253, 849 cm"!
NMR (CDCI3, 5) : 1.40-2.10 (12H, .) , 2. 01 (6H, s),
2.20 (3H, s), 4.35-4.55 (IH, m) , 4.52 (2H, s)
5-46 (IH, s), 6.79 (2H, s), 7.09 (IK, dd, 'j=5'l
3-6HZ), 7.25-7.35 (2H, m) , 7.36-7.46 (2H, irj
7.58-7.68 {2H, m)
APCI-MASS (m/z) : 447 (M+H+)
(36) 1-Cycloheptyl-l- [4- (pyrazol-l-yl ) benzyl ] -3- (2, 4, 6-
trimethylphenyl) urea
IR (KBr) : 3325, 2922, 1628, 1504, 139^ cm"^
NMR (CDCI3, 5) : 1.40-2.08 (12H, m) , 2.04 (6H, s),
2.21 (3K, s), 4.28-4.48 (IH, m) , 4.55 (2H, s),
""■'^ 6-^8 (IH, t, J=2.3.Hz), 6.81 (2F
s), 7.42-7.54 (2H, m) , 7.65-7.78 (3H, m) , 7.9^^
(IH, d, J=2.3Hz)
APCI-MASS (m/z) : 431 (M+H+)
35
(37) 1-Cycloheptyl-l- [4- ( imidazol-l-yl ) benzyl ] -3- (2,4,6-
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- 158 -
trimethylphenyl ) urea
IR (KBr) : 3310, 2922, 1637, 152C, 1305 cm"^
NMR (CDCI3, 5) : 1.38-2.10 (12K, m) , 2.05 (6H, s),
2.22 (3H, s), 4.20-4.40 (IH, m) , 4.57 (2H, s),
5 5.47 (IH, s), 6.83 (2H, s), "7.21 (IH, s), 7.28
(IH, s), 7.33-7.44 (2H, m) , 7.45-7.57 (2H, m) ,
7.85 (IH, s)
APCI-MASS (m/z) : 431 (M+H"^)
10 (38) l-Cycloheptyl-l- [4- ( l-methylpyrazol-4-yl) benzyl] -3-
(2,4, 6- trimethylphenyl) urea
IR (KBr) : 3321, 2922, 162S, 1504, 1209, 955 cm"
NMR (CDCI3, 6) : 1.38-2.08 (12H, m) , 1.99 (6H, s),
2.20 (3H, s), 3.95 (3H, s), 4.35-4.55 (IH, m) ,
15 4.50 (2H, s), 5.47 (IH, s), 6.79 (2H, s), 7.32-
7.53 (4H, m) , 7.61 (IH, s), 7.75 (IH, s)
APCI-MASS (m/z) : 445 (M+H"^)
(39) 1-Cycloheptyl-l- [ (2-phenylthiophen-5-yl ) methyl ] -3-
20 ( 2 , 4 , 6-trimethylphenyl ) urea
IR (KBr) : 3329, 2922, 1624, 151C, 758 cm" ^
NMR (CDCI3, 5) : 1.42-2.15 {12H, m) , 2.04 (6H, s] ,
2.22 {3n, s), 4.25-4.43 (IH, m) , 4.63 (2H, s),
5.82 (IH, s), 6.81 (2H, s), ^.02 (IK, d,
25 J=3.6Hz), 7.16 (IH, d, J=3.6Hz), 7.22-7.43 (3H,
m) , 7 . 50-7 . 61 (2H, m)
APCI-MASS (m/z) : 4 47 (M+H"^)
(40) 1-Cycloheptyl-l- [4- (oxazol-5-yl ) benzyl ] -3- (2, 4, 6-
30 trimethylphenyl ) urea
IR (KBr) : 3302, 2922, 1624, 1508, 1105, 941 cm" -
NMR (CDCI3, 5) : 1.38-2.08 (12H, m) , 2.03 (6H, s),
2.21 (3H, s), 4.30-4.50 (IH, m) , 4.55 (2H, s),
5.45 (IH, s), 6.81 (2H, s), 7.36 (IH, s), 7.42-
35 7.53 (2H, m) , 7.63-7.74 (2H, m) , 7.92 (IH, s)
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- 159 -
APCI-MASS (m/z) : 432 (M+H+)
(41) l-Cycloheptyl-l-[ (2-phenylfuran-5-yl)methyl]-3-(2,4,6
trimechylphenyl ) urea
IR (KBr) : 3340, 2920, 1628, 150S, 762 cm"!
NMR (CDCI3, 5) : 1.40-2.15 (12H, m) , 2.09 (6H, s),
2.23 (3H, s), 4.22-4.41 (IH, m) , 4.53 (2H, s),
5.93 (IH, s), 6.41 (IH, d, J=3.3Hz), 6.62 (IH, d,
J=3.3Hz), 6.83 (2H, s), 7.20-7.43 (3K, m) , 7.57-
7.67 (2K, m)
APCI-MASS (m/z) : 4 31 (M+.H+)
(42) l-Cycloheptyl-l-[ (5-phenylisoxazol-3-yl)methyl]-3-
(2,4, e-trimethylphenyl) urea
'^Br) : 3326, 2924, 1630, 1512, 766 cm'^
NMR (CDCI3, 6) : 1.40-2.10 {12H, m) , 2.14 (6H, s),
2.24 (3H, s), 4.05-4.25 (IH, m) , 4.56 (2H, s),
6.14 (IK, s), 6.63 (IH, s), 6.86 (2H, s), 7.40-
7.53 (3H, m) , 7.70-7.82 (2H, m)
^° APCI-MASS (m/z) : 432 (M+H+)
[4 3)
1-Cycloheptyl-l- [ ( 3-phenylpyra2ol- 5-yl) methyl ]- 3-
(2,4, 6-trimethylphenyl ) urea
IR (KBr) : 2700-3600 (br) , 2924, 1633, 1508, 1250,
1201 cm-^
NMR (CDCI3, 5) : 1.35-2.10 (12H, m) , 2.12 (6K, s),
2.23 (3H, s), 3.92-4.12 (IH, m) , 4.47 (2H, s] ,
e-24 (IH, br s), 6.50 (IH, s), 6.84 (2H, s),
7.25-7.46 (3H, m) , 7.62-7.75 (2H, m)
APCI-MASS (m/z) : 4 31 (M+H+)
(44) i-cycloheptyl-l-[ ( 4 -phenyl thiophen-2-yl) methyl ]- 3-
(2, 4, 6-trimethylphenyl) urea
IR (KBr) : 3315, 2922, 2854, 1628, 1508, 1377,
1308 cm-1
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NMR (CDCI3, 5) : 1.40-2.13 (12H, m) , 2.C3 (6H, s),
2.21 (3H, s), 4.26-4.45 (IH, m) , 4.66 {2H, s),
5.82 (IH, s), 6.81 (2H, s), 7.21-7.45 (5H, m) ,
7.50-7.60 (2H, m)
5 APCI-MASS (m/z) : 447 (M+H+)
(45) 1-Cycloheptyl-l- [4- (pyrazol- 3-yl) benzyl] -3- (2, 4, 6-
trimethylphenyl) urea
IR (KBr) : 2800-3500 (br) , 2924, 2856, 1645, 1504,
10 1240 cm"'
NMR (CDCI3, 6) : 1.38-2.1C (12H, m) , 2.00 (6K, s),
2.19 (3H, s), 4.35-4.55 (IH, m) , 4.54 (2H, s),
5.51 (IH, s), 6.60 (IK, d, J=2.3Hz), 6.78 {2K,
s), 7.42-7.53 (2H, rn) , 7.55 (IH, d, J=2.3Hz),
15 7.73-7.83 (2H, m)
APCI-MASS (m/z) : 431 (M+H"^)
(4 6) 1-Cycloheptyl-l- [4 - ( l-inethylpyrazol-3-yl ) benzyl] -3-
( 2 , 4 , 6- trimethylphenyl ) urea
20 IR (KBr) : 3406, 3331, 2924, 2856, 1647, 1502,
1236, 849, 758 cm"^
NMR (CDCI3, 5) : 1.38-2. 08 (12H, n\) , 2.00 (6K, s),
2.20 (3H, s), 3.96 (3K, s), 4.35-4.55 (IH, m) , 4.52
(2H, s), 5.50 (IH, s) , 6.54 (IH, d, J=2.3Hz), 6.78
25 (2H, s), 7.35-7.47 (3H, m) , 7.77-7.87 (2H, m)
APCI-MASS (m/z) : 445 (M+H"*")
{ 47 ) 1-Cycloheptyl-l- [4- { l-methylpyrazol-5-yl )benzyl]-3-
{2,4, 6- trimethylphenyl ) urea
30 IR (KBr) : 3296, 2922, 2854, 1628, 1506, 1385 cm"-
NMR (CDCI3, 6) : 1.38-2.10 (12H, m) , 2.02 (6H, s),
2.21 (3H, s), 3.89 (3H, s), 4.32-4.50 (IH, m) ,
4.57 (2H, s), 5.45 (IH, s] , 6.30 (IH, d,
J=1.9Hz), 6.81 (2H, s), 7.39--7.56 (5H, m) ,
35 APCI-MASS (m/z) : 445 (M+H"^)
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15
30
- 161 -
l-CycIoheptyl-l-[3-u-trityl-l„-tetra.ol-5-yl, benzyl,
J- (2, 4, 6-trimethylphenyl) urea
IR (KBr) : 3340, 2924, 2856, 1649, 1495, 1448,
1240 cm~l
NMR (CDCl^, 6) : 1 3 8-2 1 n n 9u
■i' ^-^^ -^-10 (12H, m), 1.96 (6H, s)
2.20 (3H, s), 4.30-4.50 (IH, .m) , 4.57 (9K, s)'
5.42 (IH, s), 6.77 (2H, s), 7.08-7.57 (17H, n,)'
8.05-8.18 (2K, m) *" '
(49) l-Cycloheptyl-l-[4-phenoxybenzyl-3-{4,6-
dimethoxypyrimidin-2-yl) ]urea
IR (KBr) : 3390, 2925, 2860, 1685, 1595 cm-^
NMR (CDCI3, 5) : 1-4-2.0 (12H, rr.) , 3.87 ( 6H s)
^-2-4.4 (IH, 4.51 (2H, s), 5.66 (IH, s ) ,' 6.87
(IH, s), 6.95-7.4 (9H, m)
APCI-MASS (m/z) : 477 (M+H+)
(50) l-Cyclohepi;yl-i-(4-phenylbenzyl)-3-[2,4-
bis (methylthio)-6-methylpvridin-3-yl]u-ea
^^^^^ ■■ 3360, 2925, 2855, 1660,' 1565 en."!
NMR (CDCI3, 5) : 1.45-2.1 (12H, , 2.36 (3H, si
2-45 (3H, s), 2.46 (3H, s), 4.3-4.5 (IH, xn),'4.62
(2H, s), 5.52 (IH, s), 6.59 ( IH, s), 7.3-7.7 (9H,
m)
25 APCI-MASS (m/z) : 506 (M+H+)
(51) 1- (3-Phenylbenzyl) -l-cycloheptyl-3- (2,4, 6-
crif luorophenyl ) urea
IR (KBr) : 3285, 2925, 2860, 1635, 1610, 1520 en"!
NMR (CDCI3, 5) : 1.4-2.05 (12H, m) , 4.3-4.5 (IH^
4.62 (2H, s), 5.60 (IK, s) , 6.55-6.7 (2H, m),
7.3-7. 65 (9H, m)
APCI-MASS (m/z) : 453 (M+H+ )
35
(52) 1- (2-Phenylbenzyl) -i-cycloheptyl-3- (2,4,6-
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trif luorophenyl ) urea
IR (KEr) : 3415, 3320, 3060, 3020, 2920, 2855,
1625, 1575 cm"^
NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 4.2-4.35 (IH,
m) , 4.40 (2K, s), 5.50 (IH, s), 6.55-6.75 (2K,
m) , 7.25-7 .6 {9H, m)
APCI-MASS (m/z) : 453 (M+H^)
(53) 1-Cycloheptyl-l- ( 4-phenoxybenzyl ) -3- (2, 4, 6-
10 trif luorophenyl ) urea
IR (KBr) : 3285, 2925, 2860, 1635,. 1590, 1520 cm"^
NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 4.2-4.4 (IH, m)
4.51 (2H, s), 5.58 (IH, s), 6.6-6.75 (2H, m) ,
7.0-7.4 {9H, m)
15 APCI-MASS (m/z) : 469 (M+H"^)
(54) 1-Cycloheptyl-l- ( 3-phenoxybenzyl ) -3- (2, 4, 6-
tri f luorophenyl ) urea
IR (KBr) : 3280, 2930, 2860, 1635, 1615, 1585,
2 0 152 0 cm"-'-
NMR (CDCI3, 6) : 1.4-2.0 (12H, m) , 4.2-4.4 (IH, m)
4.50 (2H, s), 5.55 ( IH, s), 6.6-6.75 (2H, m) ,
6.9-7.4 (9H, m)
APCI-MASS (m/z) : 469 (M+H"^)
25
30
;55) 1-Cycloheptyl-l- [4- (pyridin-2-yl ) benzyl ] -3- (2,4,6-
tri f luorophenyl ) urea
IR (KBr) : 3285, 2925, 2860, 1635, 1610, 1520 cm"
NMR (CDCI3, 6) : 1.4-2.1 (12H, m) , 4.25-4.4 (IH,
m) , 4.61 (2H, s), 5.59 (IH, s), 6.6-5.75 (2H,
7.2-7.3 (IH, m), 7.47 (2H, d, J=8.4Hz), 7.7-7
(2H, m), 8.02 (2H, d, J=8.4Hz), 8.65-8.75 ( IH
APCI-MASS (m/z) : 454 (M+H"^)
35
(56) 1-Benzyl-l- [ [2- ( 4-chlorophenyl ) thiazol-4-yl ] methyl ]
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(2, 4, 6-trifluorophenyl) urea
IR (KBr) : 3270, 30S0, 1665, 1640, 1615,- 1520 crr"
NMR (CDCI3, 5) : 4.54 (2H, s), 4.64 (.H, 3)
6.65-6.8 (2H, n.) , 7.3-7.4 (5H, n.) , 7.34'(1H, «
7-4-7.5 (2H, m), 7.85-7.95 (2H, m)
APCI-MASS (m/2) : 488 (M+H+ )
(57) l-(Cycloheptyl-l-f4-(pyrrol-l-yi)benzyl]-3-(2,4,6-
trif luorophenyl ) urea
^^^"^ ■• ^2^^' 2925, 2860, 1635, 1610, 15.O en,"!
NMR (CDCI3, 6) : 1.4-2.05 (12H, , 4.2-4./(iH
^-^^ ^IH, s), 6.3-6.4 (2H,'
^2^' 7.05-7.15 (2H, 7.41 (4H,
APCI-MASS (m/z) : 442 (M+H+)
15
25
30
35
(58) 1-Cycloheptyl-l- [4- ( 3-thienyl) benzyl i -3- (2, 4, 6-
trif luorophenyl ) urea
IR (KBr) : 3300, 2927, 1637, 1518, 1120, 777 c.-l
NMR (CDCI3, 5) : 1.40-2.08 (12H, , 4.2-^-4 47"
4.56 (2H, s), 5.58 (IH, s), 6.58-6.73 (.H
m). 7.30-7.50 (5H, m) , 7.57-7.70 (2H, m)
APCI-MASS (m/z) : 459 (M+H+)
(59) i-Cycloheptyl-l-[4-(2-thienyl)benzyl]-3-(2,4,6-
trifluorophenyl) urea
IR (KBr) : 3300, 2930, 1635, 1520, 11. 0 cm-I
NMR (CDCI3, 5) : 1.38-2.08 (12H, n) , 4.25-4 45 (1.
4.55 (2H, 3), 5.57 (IH, s), 6.55-6.72 (2H '
n^), 7.09 (IH, dd, J=5.1, 3.6Hz), 7.22-7.42 (4H,
m) , 7.57-7.70 (2H, n)
APCI-MASS (m/z) : 4 59 (M+H+)
Exampi
D
To a stirred suspension of 1-cycloheptyl-i- r 3- ( i -
trityl-lH-tetrazol-5-yl)benzyl] -3- (2,4, 6-
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trimethylphenyl) urea (1.46 g) in methanol (14 ml) was added
cone, hydrochloric acid (0.722 ml) . The mixture was
stirred for one hour at room temperature. Insoluble white
solid was collected by filtration, washed with methanol
5 (x2), water (x3) to give 1-cycloheptyl-l- [ 3- ( lH-tetrazol-5-
yDbenzyl] -3- (2, 4, 6-trimethylphenyl)urea (0.79 g) .
IR (KBr) : 3359, 2400-3300 (br) , 1595, 1512, 1456,
1257 cm"l
NMR (DMSO-dg, 6) : 1.35-1.90 (12H, m) , 2.06 (6H,
10 s), 2.20 (3H, s), 4.14-4.34 (IH, m) , 4.59 (2H,
s), 6.82 (2K, s), 7.46-7.66 {2H, m) , 7.80-7.90
(IH, m) , 8.00-8.08 (IH, m)
APCI-MASS (m/z) : 433 (M+H"^)
15 Ej^ampXg 7
To a solution of N-cycloheptyl-4- ( 4-
f luorophenoxy) benzylamine (2.51 g) in toluene (100 ml) were
added 3-phenoxycarbonylamino-2 , 4-bis (methylthio) -6-
methylpyridine (2.56 g) and triethylamine (2.43 g) and the
20 mixture was refluxed for 4 hours under nitrogen. The
mixrure was cooled and poured into a mixture of ethyl
acetane and water. The separated organic layer was washed
with brine, dried over magnesium sulfate and evaporated in
vacuo. The residue was purified by column chromatography
25 on silica gel to give 1-cycloheptyl-l- [ 4- (4-
f luorophenoxy) benzyl] -3- [2, 4-bis (methylthio) -6-
m.ethylpyridin-3-yl ] urea (3.89 g) .
IR (KBr) : 3379, 3080, 3055, 2924, 2856, 1651, 1568,
1529, 1497 cm~^
30 NMR (DMSO-dg, 5) : 1.4-2.0 (12H, m) , 2.39 (6H, s),
2.44 (3H, s), 4.0-4.2 (IH, m) , 4.45 (2H, s), 6.86
(IH, s), 6.93 (2H, d, J=8.5Hz), 7.0-7.1 (2H, m),
7.15-7.3 (2H, m) , 7.36 (2K, d, J=8.5Hz), 7.83
(IH, br s)
35 APCI-MASS (m/z) : 540 (M+H"*" )
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10
15
25
30
35
- 165 -
Examp1f=> s
To a solution of N-cycloheDtyl-4- ( 4-
fluorophenoxy,b.nzyla.ine (l.sv'g, in.oluene ,150 .1, „e.e
.) and tri«hyla.ine ,1.52 . and the fixture „a =
refluxed for 3 hour, under nitrogen. The fixture was
poured into a fixture of ethyl acetate and ice water, and
the separated organic layer was washed with brine, dried
over magnesium sulfate and evaporated in vacuo The
resrdue was purified by column chromatography on silica ge^
to give l-cycloheptyl-l-(4-,4-fluorophenoxy,benzylJ-3-,2 4-
dimethoxy-6-methylpyridin-3-yl)urea (1.63 g)
IR (KBr) : 33S8, 3062, 2927, 2656, 1668, 1599,
1458 cm"-
NMR (DHSO-de, 5) : 1.3-1.9 (12H, , 2.35 (3K, s)
3.67 and 3.77 (6H, s x 2), 4.0-4.2 .(IH, nt) , 4.'43
(2H, s), 6.63 (IH, s), 6.95-7.4 (8K, m)
APCI-MASS (m/z) : 496 (M+H^)
Example. Q
To a suspension of N-benzyl-3- (Dyra2ol-3-
yl)benzylamine bxMtrifluoroacetate) (2.46 g, toluene
(80 ml) were added 2, 4-bis (methylthio) -6-methyi -3-
Phenoxycarbonylaminopyridine (1.60 g) and tr.ethyl anine
(2.53 g), and the mixture was refluxed for 4.5 .hours under
-trogen. The mixture was cooled and poured rnto a ...xture
or ethyl acetate and xce water. The separated organic
layer was washed with brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was purxfied bv
column chromatography on silica gel to give 1-ben^v^-i
(pyrazol-3-yl)benzyl]-3-[2,4-bis(methylrhio)-6- " ~ ^
methylpyridin-3-yl]urea (831 mg) .
IR (KBr) : 3238, 3061, 3028, 2959, 2924, 2870, 1641,
1564, 1495 cm~I
NMR ,DMSO-de, 51 ■■ 2.42 , 6H, s,, 2.46 ,3H, s), 4.49
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(4H, br s), 6.6-6.7 (IH, m) . 6.90 (IH, s), 7.2-
7.8 (lOH, m) , 8.29 (IH, br s), 12.88 (IH, br s)
APCI-MASS (m/z) : 490 (M+H"^)
5 Example 10
The mixture of N-cycloheptyl-3- (1- tritylpyrazol-B-yl) -
benzylamine (14.63 g) and phenyl N- (2,4,6-
trifluorophenyl ) carbamate (7.64 g) and triethylamine (20
ml) in toluene (360 ml) was stirred at 100°C for one hour.
10 After cooling to room temperature, the reaction mixture was
washed with water, aqueous sodium bicarbonate, water and
brine, dried over magnesium sulfate, and evaporated in
vacuo. The residue was purified by column chromatography
on silica gel (700 g, eluting with n-hexane - ethyl acetate
15 (4:1 to 3:1)) to give 1-cycloheptyl-l- [ 3- ( l-rritylpyrazol-
3-yl)benzyl] -3- (2, 4, 6-trifluorophenyl) urea (19.6 g) .
IR (KBr) : 2900-3600 (br), 2927, 2858, 1635, 1507,
1520, 1446 cm"^
NMR (CDCI3, 6) : 1.35-2.10 (12H, m) , 4.26-4.48 (IK,
20 m) , 4.55 (2H, s), 5.57 (IH, s), 6.52-6.70 (3H,
m) , 6.75-6.97 (2H, m) , 7.10-7.45 (16H, m) ,
7.68-7.80 (2H, m)
Example 11
25 The following compounds were obtained according to
similar manners to those of Examples 7, 8, 9 and 10.
(1) 1-Cyclohexyl-l- [4- (4-f luorophenoxy) benzyl] -3- [2, 4-
bis { methyl thio) -6-methylpyridin-3-yl ] urea
30 IR (KBr) : 3377, 3084, 3057, 2927, 2856, 1653, 1566,
1533, 1497 cm~-
NMR (DMSO-dg, 5) : 1.3-1.8 (lOH, m) , 2.39 (6H, s),
2.45 (3H, s), 3.85-4.05 (IH, m) , 4.47 (2H, s),
6.86 (IK, s), 6.93 (2H, d, J=8.5Hz), 6.95-7.05
35 (2H, m) , 7.35 (2H, d, J=8.5Hz), 7.88 (IH, s)
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APCI-MASS (m/z) : 52 6 (M+H+)
(2) l-Benzyl-i-[4-(4-fluorophenoxy)benzyl]-3-[2,4-
bis (niethylthio) -6-inethylDvridin-3-yT ) urea
5 IR (KBr) : 3307, 3062, 3029, 2999, 2922, 1735, 1660,
1564, 1497 cm~^
NMR (DMSO-dr- 5) • ■? ao /
^6, ■ 2.42 (oh, s), 2.46 (3H, s), 4 43
(2H, s), 4.46 (2H, s), 6.89 (IH, s), 6.9-7.4
(13H, m) , 8.26 (IH, s)
10 APCI-MASS (m/z) : 526 (M+H+)
(3) l-Cycloheptyl-l-(4-phenoxybenzyl)-3-[2,4-
bis (methylthio) -6-methylpyridin-3-vl j u^ea
IR (KBr) : 3371, 2922, 2856, 1653, 1485, 1219 cm-1
^R (CDCI3, 5) : 1.35-2.10 (12H, , 2.36 (3H, s)
2-45 (3H, s), 2.46 (3K, s), 4.22-4.42 (IH, m) '
^•55 (2H, s), 5.49 (IH, s), 6.59 (IH, s), 6.95-
7.15 (5H, m) , 7.24-7.46 (4H, m)
APCI-MASS (m/z) : 522 (M+H+)
15
20
30
35
(4
l-Cycloheptyl-l-[4-(4-bromophenoxy)benzvl]-3-[2 4-
bis (methylthio) -6-inethylpyridin-3-yi] urea
IR (KBr) : 3377, 2924, 2852, 1668, 1481, 1238 cm-1
NMR (CDCl-., 5) • 1 4 0-9 in
25 ^ ^-1° ^12ri, m) , 2.37 (3H, s),
2-46 (3H, s), 2.47 (3H, s), 4.25-4.40 (ip m)
4-55 (2H, s), 5.47 (IH, s), 6.60 (IH, s), 6.80-
7.08 (4H, m), 7.35-7.50 (4H, m)
APCI-MASS (m/z) : 600, 602 (M+H+)
(5) 1-Benzyl-l- [ 4- ( 4 -bromophenoxy ) benzyl ] -3- [2, 4-
bis (methylthio) -6-inethylpyridin-3-yl]u-ea
IR (KBr) : 3200-3700 (br) , 2922, 1662, 1564, 1481,
12 3 6 cm 1
NMR ,CDCl3. 6, : 2.39 ,3H, s,, 2.47 ,3„, 3,, , 49
(3H, s), 4.61 (2H, s), 4.63 (2H, s), 5.68 (IH,
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s), 6.62 (IH, s), 6.82-7.05 (4H, m) , 7.25-7.50
{9H, m)
APCI-MASS (m/z) : 594, 596 (M+H"^)
5 (6) 1-Cycloheptyl-l- [ 4- ( 4-bromophenoxy) benzyl ] -3- [2 , 4-
dimethoxy-6-methylpyridin-3-yl ] urea
IR (KBr) : 3100-3700 (br) , 2926, 2856, 1668, 1597,
1504, 1481, 1240 cm"^
NMR (CDCI3, 5) : 1.40-2.10 (12H, m) , 2.38 (3H, s),
10 3.79 (3H, s), 3.83 (3H, s), 4.25-4.40 (IH, m) ,
4.52 (2H, s) , 5.43 {IH, s), 6.36 (IH, s), 6.82-
7.06 (4H, m) , 7.32-7.50 {4H, m)
APCI-MASS (m/z) : 568, 570 (M+H+)
15 (7) 1-Benzyl-l- [4- (4-bromophenoxy) benzyl] -3- [2, 4-
ciimethoxy-6-methylpyridin-3-yl ] urea
IR (KBr) : 3200-3400 (br), 2997, 1637, 1595, 1506,
1365 cm"^
NMR (CDCI3, 5) : 2.39 (3H, s), 3.80 (3H, s), 3.85
20 {3H, s), 4.60 {4H, s), 5.64 (IH, s), 6.38 (IH,
s), 6.80-7.05 {4H, m) , 7.22-7.50 (BH, m)
APCI-MASS (m/2) : 562, 564 (M+H"^ )
Example 12
25 To a mixture of 1 -cyclohept y 1- 1 - [ 3- ( 1- t r i t ylpyr azol- 3-
yl) benzyl] -3- (2, 4, 6-trifluorophenyl) urea (17.6 g) and
anisole (35 ml) was added tri f luoroacet ic acid (70 ml) .
The mixture was stirred at eO'C for 3 hours and cooled to
room temperature. The excess tr i f luoroacetic acid was
30 removed in vacuo. To the residue was added water and ethyl
acetate. The mixture was basified with 5N-sodium hydroxide
under ice cooling and extracted with ethyl acetate. The
organic layer was washed with water, and brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
35 purified by column chromatography on silica gel (530 g,
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eluting with n-hexane - ethyl acetate (2:1 to 1:2)) to give
l-cycloheptyl-l-[3-(pyrazol-3-yl)ben2yIl-3- (2,4, 6-
trifluorophenyl) urea (10.71 g) .
IR (KBr) : 3500-2600 (br) , 2927, 2858, 1635, 1520,
^ 1448, 1248, 1120 cm-^
NMR {CDCI3, 5) : 1.30-2.10 (12H, , 4.26-4.46 (IK,
m), 4.59 (2H, s), 5.63 (IH, s), 6.53-6.73 (3H,
m), 7.30-7.50 (2H, m) , 7.63 (IH, d, J=2.3Hz),
7.65-7.80 (2H, m)
APCI-MASS (m/z) : 443 (M+H")
ExamlP 13
To a solution of N-cycloheptyl-4- (4-f luorophenoxy) -
benzylamine (1.57 g) in toluene (100 ml) were added 3-
phenoxycarbonylaznino-2,4,6-trimethylpyridine (2.56 g) and
triethylamine (1.52 g) , and the mixture was refluxed for 3
hours under nitrogen. The mixture was cooled and noured
into a mixture of ethyl acetate and water. The seoaratea
organxc layer was washed with brine, dried over maanesrum
sulrate and evaporated in vacuo. The residue was Durified
t5y column chromatography on silica gel to give 1-
cycloheptyl-l-[4- (4-fluorophenoxy) benzyl ] -3- (2,4, 6-
trimethylpyridin-3-yl) urea (1.83 g) .
IR (KBr) : 3313, 2924, 2856, 1630, 1603, 1^97 en"!
25 NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 2.06 (3H, s),
2.24 (3H, s), 4.05-4.25 (IK, m) , 4.48 (2H, s),
6-98 (IH, s), 6.9-7.1 (4H, m) , 7.2-7.4 (4H, mj,
7.66 (IH, s)
APCI-MASS (m/z) : 476 (M+H+)
15
20
30
35
Example 14
To a solution of N-cycloheptyl-4- ( 4 -f luoroohenoxy ) -
benzylamine (2.51 g) in toluene (120 ml) were added 4-
chloro-6-.methyl-2-methylthio-3-phenoxycarbonylaminopvridine
(2.47 g) and triethylamine (2.43 g) at room te.mperature and
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the mixture was refluxed for 2.5 hours under nirrogen. The
mixture was poured into a mixture of ethyl acetate and ice
water and the separated organic layer was washed with
brine, dried over magnesium sulfate and evaporated in
5 vacuo. The residue was purified by column chromatography
on silica gel to give 1-cycloheptyl-l- [ 4- ( 4-f luorophenoxy) -
benzyl ] -3- ( 2-chloro-6-methyl--4-methylthiopyridin-3-yl ) urea
(2.76 g) .
IR (KBr) : 3371, 3299, 2924, 2852, 1655, 1576,
10 1500 cm~^
NMR (DMSO-dg, 5) : 1.3-1.8 (12H, m) , 2.43 {6H, s),
4.0-4.2 (IH, m) , 4.46 {2H, s), 6.9-7.5 {9H, m) ,
8.07 (IH, br s)
15 F.xample 15
To a solution of N-benzyl-3- {pyrazol-3-yl ) benzylamine
(54.0 g) and triethylamine (143 ml) in toluene (1.35 P) was
added 2, 4-bis (methylthio) -3-phenoxycarbonylamino-6-
methylpyridine (62.4 g) at room temperature and stirred for
20 24 hours. The resulting precipitate was collected by
filtration and recrystallized from dichloromethane -
methanol - n-hexane to give 1-benzyl-l- [ 3- (pyrazol-3-
yl) benzyl] -3- [2, 4 -bis (methylthio) - 6-methylpyridin- 3-yl ] urea
(51 . 0 g) .
25 mp : 209-210°C
IR (KBr) : 3392, 3246, 2918, 1549, 1489, 1228,
1093 cm~^
NMR (DMSO-dg, 5) : 2.42 (&H, s), 2.47 (3K, s), 4.49
(4H, s), 6.66 (IH, br s), 6.90 (IK, s), 7.18-7.90
30 (lOH, m) , 8.30 (IH, s), 12.89, 13.30 (total IH,
each br)
APCI-MASS (m/z) : 490 (M+H"*")
Example 16
35 To a solution of N-benzyl- [ 4 -( 4-bromophenQxy) benzyl ] -
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10
15
20
!5
0
anine (1.64 g) and 2, 4, 6-trimethylphenyl-3-
phenoxycarbonylaMinopyridine (2.20 g, m N N- ^
dx^ethylfo^lda ,50 .1, was added triethWan-ine (2 53 a
n. rogen. The .i«ure „as cooled and et.vl acetate 50
f-ltered oft, and the filtrate was washed with wate- ard
br.ne, dt.ed over -..agneslu. sulfate and evaporated m
vacuo The residue was pur.f.ed .y colu..„ ;hro„ato raphy
on sx ca gel to give 1-benzyl-l- f 4- (4-bro.oohenoxy) -
benzyl,-3-,2.4,6-tri.ethylpyridin-3-yl,urea ',2 51 g
IR <KBr) . 3406, 3313, 2856, 1714, '1632, '1572
1495 cm-i
(-SO-.,, 5) : ..OS s), 2.2e s), 2.35
(3H, s), 4.53 (2H, s), 4.57 (2H, s), 6.95-7 15
m), 7.3-7.6 (9H, m) , 8.05 (IH, br s)
APCI-MASS (m/z) : 531
Example 17
TO a solution of N-cycloheptyl-4- ,4-fluorophenoxv) -
^enzyla^ine (1.25 g, m toluene ,80 „l, were added 4 6-
b.s,„ethylth.o,-2-„ethyl-s-pheno>:ycarbonyla.,i„opyr.,;dine
(-.29 g, and tr.ethyla.ine ,1.21 g,, and the nrxture was
refluxed for 2 hours under nitrogen. The .ixtu-e was
poured rnto a fixture of ethyl acetate and ice water, and
the separated organic layer was washed with brine
over magnesium sulfate and evaporated in vacuo.
dried
vduuo. The
resrdue was purified by column chromatography on silica gel
to grve l-oy=Ioheptyl-l-t4-(4-fluorophenoxy,ben.yl,-3- 4 :
brs,methylthio,-2-methylpyrimidin-5-yljurea (i 33 g,
" (KBr, : 3255, 2926, 2856, 1653, 1522, ,457 .^m-l
NMR (DMSO-d„ 6, : 1.4-1.9 ,i2H, m,, 2.43 [sH, s,
2-56 ,3H, s), 3.95-4.1 (IH, m) , 4.46 I7p 3,
6-9-7.4 ,8H, n), 8.00 ,1K, br s I
APCI-MASS ,m/z) : 529 (M+H* )
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Example 18
To a solution of 1-cycloheptyl-l- [ 4- (3, 5-di-tert-
butyl-4-methoxymethoxyphenoxy ) ]benzyl-3- (2, 4, 5-
trimethylphenyl ) urea (860 mg) in methanol (8.6 ml) was
5 added cone, hydrochloric acid (0.91 ml), and the mixture
was stirred at room temperature for 2 hours and at 40°C for
3.5 hours. The mixture was poured into a mixture of ethyl
acetate and ice water, and neutralized by addition of
saturated sodium bicarbonate aqueous solution. The
10 separated organic layer was washed with water and brine,
dried over magnesium sulfate and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
to give 1-cycloheptyl-l- [4- (3, 5-di-tert-butyl-4-
hydroxyphenoxy ) benzyl ] -3- ( 2 , 4 , 6- trimethylphenyl ) urea (4 95
15 mg) .
IR (KBr) : 3639, 3404, 3323, 2956, 2923, 2860, 1651,
1593, 1504 cm"l
NMR (CDCI3, 6) : 1.41 (18K, s), 1.5-2.1 (12H, m) ,
1.98 {6H, s), 2.22 (3H, s), 4.25-4.4 (IH, m) ,
20 4.45 (2-H, s), 5.03 (IH, s), 6.80 (2H, s), 6.86
(2H, s), 6.93 (2H, d, J=8.5H2), 7.55 {2K, d,
J=8 . 5Hz)
APCI-MASS (m/z) : 585 (M+K"^)
25 Example 19
To a solution of 1-cycloheptyl-l- [ 4- ( 4-
f luorophenoxy ) benzyl] -3- [2, 4-bis (methylthio) -6-
methylpyridin-3-yl ] urea (22.11 g) in dichloromethane (150
m.l ) was added dropwise a solution of m-chloroperbenzoic
30 acid (26.51 g) in dichloromethane (600 mg) at room.
temperature over 2 hours. The mixture was stirred at room
temperature for 23 hours. The precipitates were removed by
filrration and the filtrate was washed with dilute sodium
bicarbonate aqueous solution and brine, dried over
35 magnesium sulfate and evaporated in vacuo. The residue was
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purxfied by colmnn chroniatography on silica gel to g.ve 1-
cycioheptyl-l-[4-(4-fluorophenoxy)benzyI]-3-[2 4-
bis(methylsulfonyl)-6-methylpyridin-3-yl]urea '(20 g,
IR (KBr) : 3361, 3074, 3041, 3016, 2927, 2860, 1740,
1664, 1500, 1325, 1159, 1128 cm--
3' °^ • 2.2 (12H, m), 2.66 (3H, s), 3.19
s), 3.30 (3H, s), 4.55 (2H, s), 6.95-7 05
(6H, m), 7.34 (2H, d, J=8.6Hz) 7.26 (IH, s), 7 85
(IH, s)
.10 APCI-MASS (m/z) : 604 (M+H+)
Example ?n
To a solution of 1-cycloheptvl-l- [4- ( 4-
fl^uorophenoxy) benzyl ] -3- [2, 4-bis (methylthio) -6-
-ethylpyridin-3-yl]urea (4.75 g) xn dichloro.ethane (50 xnl )
was added dropwise a solution of .-chloroperbenzoic ac.d
(-^-96 g) in dichloromethane (80 ml) at room temperature
The mrxture was stirred at room temperature for 20 hours
The mxxture was washed with dilute sodium bicarbonate
aqueous solution and brine, dried over magnesium sulfate
and evaporated in vacuo. The residue was ouri^ie^^ bv
column Chromatography on silica gel to give 1-cvcloheor vl-
1- [4- (4-fluorophenoxy)benzyl]-3- [2, 4-bis (methylsul - nv i J - 6-
metnylpyridin-3-yl]urea (2.15 g).
^^^"^ ^251, 2927, 2858, 1738, 1651, 1498, 1055,
1036 cm~l
NMR (CDCI3, 5) : 1.4-2.0 (12H, m) , 2.59 (3H, s) ^ 8.
and 2.94 (total 3H, s), 2.98 (3H, s), 4. 0-4 .
(2H, m), 4.51 (2H, br s), 6.9-7.1 (7H, m) , 7.25-
7.35 (2H, m) , 7.77-7.79 (total IK, s)
APCI-MASS (m/z) : 572 (M^.^:+)
Examn1p> 7 ■)
To a suspension of 1-cycloheptyl-l- [ 3- (i_
tritylpyrazol-4-yl)benzyl] -3- (2, 4, 6-trimethylphenyl] urea
20
30
35
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(800 mg) in anisole (2 ml) was added trif luoroacetic acid
(6 ml) and the mixture was stirred at 100°C for 2 hours.
The mixture was evaporated in vacuo and poured into a
mixture of ethyl acetate and water and adjusted to pH ca. 9
5 by addition of sodium hydroxide aqueous solution. The
separated organic layer was washed with brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give 1-
cycloheptyl-1- [3- ( pyrazol- 4 -yl ) benzyl ] -3- (2, 4, 6-
10 trimethylphenyl ) urea (102 mg) .
IR (KBr) : 3400, 3207, 2926, 2856, 1635, 1608,
1510 cm"-
NMR {DMSO-dg, 6) : 1.3-1.9 (12H, m) , 2.08 (6H, s),
2.20 (3H, s) , 4.1-4.3 (IH, m) , 4.51 (2H, s), 6.83
15 (2H, s), 7.1-7.5 (5K, m) , 7.84 (IH, s), 8.11 (IH,
s) , 12. 95 (IH, br s)
APCI-MASS (m/z) : 431 (M+H"^)
Example 22
2 0 The following compounds were obtained according to a
similar manner to that of Example 1, 2, 3 or 4 .
(1) 1-Cycloheptyl-l- [4- ( 4-chlorophenoxy ) benzyl] -3- (2, 4, 6-
t rimethylphenyl ) urea
25 IR (KBr) : 3410, 2920, 2850, 1660, 1590, 1505,
14 85 cm"l
NMR (CDCI3, 5) : 1.5-2.1 (12H, m) , 2.00 (6H, s), 2.22
(3H, s), 4.3-4.45 ( IH, m) , 4.48 (2H, s), 5.6-5.8
(IH, br), 6.81 (2H, s), 6.92 {2H, d, J=8.5Hz),
30 7.00 (2H, d, J=8.5Hz), 7.28 (2n, d, J=8.4Hz),
7.38 (2H, d, J=8.4Hz)
35
(2) 1-Cycloheptyl-l- [4- ( 3-f luorophenoxy) benzyl] -3- (2, 4, 6-
trimethylphenyl ) urea
mp : 127-128°C
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- 175 -
IR (KBD : 292.. 2856, 162., 1605, 1506, 1485 c^"!
,CDCl3, 5, : 1.35-2.10 a2H. 2.01 ,6H, s,
2-22 (3H, s), 4.30-4.50 (IK, ml, 4.50 (2H, s,'
5.« (IH, s), 6. 60-6.88 (3H, m) , 6.79 (2H, s)'
^■00-7.10 ,2H, m), 7.20-7.35 ,XH, „) , 7.36-7 47
<2H, m)
APCI-MASS (iti/z) ; 475 (M-.«-)
<3, ^-^J=^°heptyl-l-[4-,4-trifluoro.ethylphenoxy,.enzyl,-
(-^^ 4, 6-trimethylphenyl) urea
(4)
20
35
mp : l^e-l^T'c
(KBD : 2924, 2856, 1628, 1504, 1327, 1246 cm-l
NMR {CDCI3, 6) : 1 40-2 10 ( l 9u . .
J ^.^u ^.ij (I2h, m) , 2.03 (6H, s)
15 ^-^^ ^-30-4.50 (IH, m), 4.51 (2» s)'
5-^7 (IH, s), 6.83 (2H, s) , 6.95-7.13 (4F,' n.) '
7-35-7.50 (2H, m) , 7.53-7.65 (2K, zn)
APCI-MASS (m/z) : 525 (MxH+)
I-Cycloheptyl-l- f 4- (3, ^-.ethylenedxoxyphenoxy , benzvl 1 -
- (2, 4, 6-trimethylphenyl)urea
mp : 125-126°C
IR (KBD : 3323, 2922, 2854, 1628, 1506, 148^ c-^-l
(CDCI3, : 1.38-2.10 (12H, , 1.99 ..^^
2.22 (3H, s), 4.33-4.50 (IH, m) , 4.46 (2^ s)
5.46 (IH, s), 5.98 (2K, s), 6.47 (1h, dd, 'j= '
2^4Hz), 6.56 (IH, d, J=2.4Hz), 6.76 (IH, d
J-8.3HZ), 6.81 (2H, s ) , 6.90-7.00 (2H, xn', , ' 7
7.38 (2H, m)
APCI-MASS (m/z) : 501 (M+H^)
1-Cycloheptyl-l- [4- 5_di_tert-butyl-4-
methoxymethoxyphenoxy) ]benzyl-3- (2,4,6-
trimethylphenyl ) urea
IR (KBr, : 3406, 3323, 2956, 2924, 2862. 1641, 1589
1504 cm--
3,
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NMR (CDCI3, 6) : 1.41 (18H, s), 1.4-2.2 (14H, m) ,
1.99 (6H, s), 2.22 (3H, s), 3.62 and 3.65 (total
3H, s) , 4.3-4.5 flH, m) , 4.46 (2H, s), 4.86 and
4.92 (total 2H, s), 6.80 (2H, s), 6.95-7.1 (4K,
5 m) , 7.4-7.5 (2H, m)
( 6 ) 1-Cycloheptyl-l- [4- ( 4-f luorophenoxy) phenyl ] -3- ( 2 , 4, 6-
t rime thy Iphenyl ) urea
IR (KBr) : 3425, 2925, 2860, 1670, 1610, 1500 cm"^
10 NMR (CDCI3, 6) : 1.3-1.7 and 1.9-2.1 (12H, m) , 2.12
(6H, s) , 2.22 (3H, s), 4.45-4.65 (IH, m) , 5.30
(IH, br s), 6.82 (2K, s), 7.0-7.3 (8H, m)
APCI-MASS (m/z) : 4 61 (M+H"^)
15 (7) 1-Benzyl-l- [4- (4-f luorophenoxy) benzyl] -3- (2, 4, 6-
t rimethylphenyl ) urea
IR (KBr) : 3307, 3062, 3030, 2918, 1633, 1608, 1510,
1497 cm'^
NMR (CDCI3, 6) : 2.00 (6H, s), 2.22 (3H, s), 4.62
20 (4H, s), 5.68 (IH, s), 6.82 (2H, s), 6.9-7.1 (6H,
m) , 7.3-7.45 (7H, m)
APCI-MASS (m/z) : 469 (M+H"^)
( 8 ) 1-Pentyl-l- [4- ( 4-f luorophenoxy ) benzyl ] -3- (2 , 4 , 6-
25 trimethylphenyl) urea
IR (KBr) : 3292, 2958, 2920, 2856, 1632, 1608,
1498 cm"l
NMR (CDCI3, 6) : 0.90 {3H, t, J=6.3Hz), 1.25-1.45
(4H, m) , 1.6-1.8 (2K, m) , 2.09 (6H, s), 2.30 (3H,
30 s), 3.39 (2H, t, J=7.4Hz), 4.55 (2K, s), 5.74
(IK, br s), 6.84 (2K, s), 6.9-7.1 (6H, m) , 7.30
(2H, d, J=8.4Hz)
APCI-MASS (m/z) : 449 (M+H"^ )
35
(9) 1-Cyclohexyl-l- [4- ( 4-f luorophenoxy ) benzyl] -3- (2, 4, 6-
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25
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- 177 -
trimethylphenyl ) urea
IR (KBr) : 3296, 2958, 2922, 2890, 1624, 1520,
1487 cin~l
NMR (CDClo, 5) • 1 3-7 0 nOH - r.
3' ^-^ -^-u (lOri, m) , i.99 (6H, s) 2 2
(3H, s), 4.25-4.45 (IH, m) , 4.47 (2H, s), 5^4'
(IH, br s), 6.81 (2.H, s), 6.9-7.1 (6H, n.) , 7.35
(2H, d, J=8.5Hz)
APCI-MASS (m/z) ; 461 (M+H+)
(10) 1-Cyclopentyl-l- f 4" ( 4-f luorophenoxy ) benzyl J -3- (2,4, 6-
trimethylphenyl ) urea
IR (KBr, : 3,00, 3304, 3074, 2933, 2850, 1657, 1608
1495 cm-1
NNR (CDCI3, 5) : 1.5-1.3 and 2.0-2.15 (8H, , 2. 00
s), 2.22 (3H, s), 4.47 (2H, s), 4.7-4 9 (IK
5.35 (IH, br s), 6.82 (2.H, s), 6.9-7.1 ( 6H
^) > 7.33 (2H, d, J=8.5Hz)
APCI-MASS (m/z) : 447 (M+H+)
(11) 1-Cycloheptyl-l- [4- ( 4-fluorophenoxy) benzyl ] -3- (2,4, 6-
trif luorophenyl ) urea
IR (KBr) : 3284, 2929, 2858, 1633, 1612, 1518,
1497 cm-1
NMR (CDCI3, 5) : 1.4-2.1 (12H, m) , 4.25-4 4^, (IH
4.50 (2H, s), 5.58 (IH, s), 6.55-6.7 (2H,' m)
6.9-7.1 (6H, m), 7.25-7.4 (2H, m)
APCI-MASS (m/z) : 487 (M+H+)
(12) 1-Benzyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3404, 3207, 3060, 3029, 2967, 2918, 2858,
1635, 1608, 1510 cm"-
NMR (DMSO-dg, 5) : 2.09 (6H, s), 2.21 (3H, s), 4.57
(2K, s), 6.0-6.05 (IH, m) , 6.84 (2H, s), 7.2-7 5
(7H, m), 7.65-7.8 (3H, m) , 7.87 (IK, s), 12. 89'
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(IH, br)
APCI-MASS (m/z) : 425 (M+H"^)
(13) 1-Benzyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- (2, 4, 6-
cri f luorophenyl ) urea
IR (KBr) : 3246, 1637, 1522 cm"^
NMR (DMSO-dg, 5) : 4.54 (4H, s), 6.65 (IH, br s),
7.2-7.5 {4H, m) , 7.7-7.9 (3H, m) , 8.47 (IH, br
s), 12.90 and 13.34 (total IH, br s)
APCI-MASS (m/z) : 437 (M+H"^)
(14) 1-Cycloheptyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- (2, 4, 6-
tri f luorophenyl ) urea
IR (KBr) : 3226, 3062, 2927, 2858, 1635, 1612,
15 1518 cm"^
NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 4.0-4.2 (IH, m) ,
4.55 (2H, s), 6.63 (IH, d, J=1.9Hz), 7.15-7.5
(4H, m) , 7.6-7.8 (3H, m) , 8.10 (IH, br s)
APCI-MASS (m/z) : 444 (M+H"^)
20
(15) 1-Cyclohexyl-l- [3- (pyrazol-3-yl) benzyl ] -3- (2, 4, 6-
t rime thy Iphenyl ) urea
IR (KBr) : 3226, 2929, 2856, 1635, 1608, 1510 cm"^
NMR (DMSO-dg, 5) : 1.3-1.8 (lOH, m) , 2.08 (6H, s),
25 2.20 (3H, s), 4.0-4.2 (IH, m) , 4.57 (2H, s), 6.62
(IH, br s), 6.83 (2H, s), 7.2-7.45 (2H, m) , 7.55-
7.85 (3H, m) , 12.86 (IH, br s)
APCI-MASS (m/z) : 417 (M+H"^)
30 (16) 1-Cyclopentyl-l- [3- (pyrazol-3-yl) benzyl] -3- (2, 4, 6-
trimethylphenyl) urea
IR (KBr) : 3188, 2956, 2870, 1635, 1608, 1510 cm"-
NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 2.08 (6H, s),
2.20 (3H, s), 4.45-4.6 (IH, m) , 4.56 (2H, s),
35 6.63 (IH, br s), 6.83 (2H, s), 7.15-7.45 (2K, m) ,
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- 179 -
7-55-7.85 (5H, m) , 12.87 (IH, br s)
APCI-MASS (m/z) : 403
(17) l-Cycloheptyl-l-f3-a-tr.tylpyrazol-4-yI,benzyl]-3-
{2,4, 6-trimethylphenyl) urea
IR (KBr, : 3408, 3323, 3059, 303C, 2S24, 2856, 16.=
1608, 1562 cm-1
NMR (DMSO-d^, 6) • 1 4-1 q n9M
^ ' --^ (12ri, m), 2.00 (6H, s)
2-20 (3H, s), 4.0-4.2 (IH, m) , 4.4B (2H, s) 6
s), 7.1-7.5 (19H, , 7.70 (IH, 3), 8.0.
(IH, s)
APCI-MASS (m/z) : 673 (M+H+)
(18) l-Cycloheptyl-l-M-(I-trltylpyrazol-4-yl)benzvl]-3-
{2,4, e-trimethylphenyl) urea
IR (KBr) : 3406, 3323, 3057, 3030, 2924, 2854, 1640
1568 cm-1
m-.R ,DMSO-d„ 5, : 1.40-2.0 ,12H, , 2.0B ,6H, s,
-'•20 !3K, s), 4.05-4.25 flH, 4.47 ^^^^
6.83 (2H, s) 7 ni=,-7 ^ > --^
1 — , s;, /.ub 7.15 ,cd, mj-, 7.25 (2K, d,
J=8.2nz}, 7.3-7.4 (IIH, n>.) , 7.49 (2H, d,
J=8.2Hz], 7.78 (IH, s), 8.07 ;iK, s)
APCI-MASS (m/z) : 673 (M^.H+)
(19) i-Cy^l°heptyl-l-f3-(l-methylpyrazoI-4-yl)benzyl]-3-
(2, 4, 6-trimethylphGnyl ) urea
IR (KBr) : 3408, 2924, 2856, 1637, 1610, 1497,
1234 cin~l
NMR (CDCI3, 5) : 1.38-2.10 (12H, , 1.98
2-20 (3H, s), 3.95 (3H, s), 4.36-4.56 (IH, n) '
4-52 (2H, s), 5.48 (IH, s), 6.78 (2H, s), 7 20-
7-52 (4H, ra), 7.62 (IH, s), 7.75 (IH, s)
APCI-M-ASS (m/z) : 44 5 (M-H^)
(20) 1-Cycloheptyl-l- f 3- ( l-methylpyrazol-3-yi ) benzyl] -3-
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(2,4, 6-trimethylphenyl ) urea
mp : 142-143°C
IR (KBr) : 3346, 2924, 2854, 1630, 1502, 1246 cm""-
NMR (CDCI3, 5; : 1.35-2.10 (12H, in), 1.9" (6K, s),
2.19 {3H, s), 3.95 (3H, s), 4.38-4.58 (IH, m) ,
4.55 (2H, s), 5.49 (IH, s), 6.53 (IK, d,
J=2.2Hz), 6.77 (2H, si, 7.30-7. 50 (31-1, m) , 7.65-
7,88 (2K, rci)
APCI-MASS (m/z) : 445 (M+H"^)
(21 ) 1-Cycloheptyl-l- [ 3- ( l-inethylpyrazol-5-yl ) benzyl ] -3-
( 2 , 4 , 6-trimethylphenyl ) urea
rap : 171-172°C
IR (KBr) : 3307, 2924, 2856, 1626, 1506, 1254 cm" -
15 NMR (CDCI3, 5) : 1.38-2.10 (12H, m) , 2.00 (6H, s),
2.21 {3H, s), 3.89 (3H, s), 4.30-4.50 (IH, m) ,
4.57 (2H, s), 5.46 (IH, s), 6.29 (IH, d,
J=1.9Hz), 6.80 (2H, 3), 7.25-7.56 (5H, m)
10
20
APCI-MASS (m/z) : 44 5 (M-i-H"*"
(221 1-Cycloheptyl-l- [3- ( imidazol-4-yl ) benzyl] -3- (2,4, 6-
t r imethylphenyl ) urea
IR (KBr) : 3140 (br) , 2924, 2S56, 1635, 1608, 1497 cm'
NMR (DMSO-dg, 5) : 1.25-1.90 (12n, m) , 2.07 (6H, s),
25 2.20 (3H, s), 4.07-4.27 (IH, m) , 4.52 (2H, s),
6.82 (2K, s), 7.08-7.80 (7H, m) , 12.13, 12.53
(total IH, each br)
.2.PCI-M.2.SS (m/z) : 431 (M+H"^ )
30 (23) 1-Cycloheptyl-l- [4- (5-methyl-l, 3, 4-oxadiazol-2-
yl ) benzyl ] -3- ( 2 , 4 , 6-trimethylphenyl ) urea
mp : 123-124°C
IR (KBr) : 3319, 2924, 2856, 1622, 1500, 1243 cm" ^
NMR (CDClg, 0) : 1.35-2.10 (12H, m) , 2.04 (6H, s),
35 2.22 (3H, s), 2.62 (3H, s), 4.20-4.40 (IH, m) ,
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/-59 C2H, m) , 7.98-8.08 (2H, m)
APCI-MASS (in/2) ; 447 (M-fH+)
5 (24) l-Cycloheptyl-l-H-(5-.ethyl-4H-l,2,4-tr.azol-3-
yl) benzyl] -3- (2,4, 6-trimethylphenyl) urea
mp : 1'32-145°C
IR (KBr, : 2600-3700 <br,, 2924, 2856, 1633, 1608
1558, 1504, 1238 cir-^
^° (CDC13, 5) : 1 38-2 IS n 9w
J ^.JB ^.Ib fl2H, m) , 1.90 (6F s)
2-27 (3H, s), 2.16 (3H, s), 4.37-4.57 (1k, n.) '
^•58 (2H, s), 5.59 (IH, 3), e.71 ,2H, s), 7 4^-
7.57 (2H, m), 8.05-8.17 (2H, m)
APCI-MASS (m/z) : 44 6 (M^H+ )
.5
(25) l-Cycloheptyl-i-M-(4-benzyl-5-methyl-4H-. 2 4-
trxazol-3-yI)benzyl]-3-(2,4,6-tr...ethylpheny;)urea
mp : 193-194°C
IR (KBr) : 3296, 2924, 2856, 1626, 1506, 1252
847 cm-1
NMR (CDCl-., 6) • 1 35-7 ns / t oli
' ^-^^ 2.05 (12H, m), 2.00 ( 6H s)
2-21 (3H, s), 2.39 (3K, s), 4.20-4.40 (IK,' m) '
^-^^ (IH, 3), 6.8^
25 . ' '-^^-^-O^ (2H, m), 7.30-7.60 (7H, ra)
25 APCI-MASS (in/z) .- 536 (.M+H+)
(26) -™eptyl-l-,3-(2-.ethyl-2H-tet.azol-5-yl).enzyl]-
-^-(2,4, 6-trimethylphenyl ) urea
mp : 175-176°C
^^^^^ ■• ^^27, 2922, 2856, 1628, 1500, I.55 c."!
NMR (DMSO-d,, 6, : 1.30-1.90 a2H, .) , 2 . ol ( 6K s)
2-20 (3H, s), 4.12-4.30 (IK, m) , 4.4^ (3H s)
-^-59 (2K, s), 6.83 (2K, s), 7.40-7.65 (3H,' m) '
_ 7.85-7.95 (IH, m) , 8.06 (IH, s)
35 APCI-MASS (m/z) : 447 (M+H^)
20
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- 182 -
(27) 1-Cycloheptyl-l- [3- ( l-methyl-lH-tetrazol-5-yl ) benzyl ]
3- {2, 4, 6-trimethylphenyl) urea
mp : 171-173°C
IR (KBr) : 3323, 2924, 2854, 1626, 1502, 1444,
1254 cm~l
NMR (DMSO-dg, 5) : 1.40-1.90 (12H, m) , 2.06 (6H, s),
2.20 {3H, s), 4.16 (3H, s), 4.10-4.28 (IH, m) ,
4.59 (2H, s), 6.83 (2H, s), 7.54-7.80 {5H, m)
APCI-MASS (m/z) : 447 (M+H"^)
(28 ) 1-Cycloheptyl-l- [4- ( 1, 2, 4- IH-triazol- 1 -yl ) benzyl ] -3-
(2,4, 6-trimethylphenyl) urea
IR (KBr) : 3310, 2924, 2856, 1639, 1518, 1277,
1147 cm"^
15 NMR (CDCI3, 5) : 1.40-2.10 (12H, m) , 2.07 (6H, s),
2.22 (3H, s), 4.20-4.40 (IH, m) , 4.58 (2H, s),
5.49 (IH, s), 6.82 (2K, s), 7.50-7.60 (2H, m) ,
7.64-7.74 (2H, m) , 8.11 (IH, s), 8.55 (IH, s)
APCI-MASS (m/z) : 432 (M+H+ )
20
(29) 1-Cycloheptyl-l- [4- (1, 2, 3- IH- tr iazol- 1-yl ) benzyl ] -3-
(2, 4, 6-trimethylphenyl) urea
IR (KBr) : 3331, 2924, 2856, 1637, 1498, 1319, 1234,
10 34 cm"^
25 NMR (CDCI3, 5) : 1.40-2.10 (12H, m) , 2.07 (6H, s),
2.22 (3H, s), 4.20-4.38 (IH, m) , 4.60 (2H, s),
5.55 (IH, s), 6.83 (2H, s), 7.52-7.61 (2H, m) ,
7.70-7.80 (2H, m) , 7.86 (IH, s), 8.00 (IH, s)
APCI-MASS (m/z) : 432 (M+H"^)
30
(30) 1-Cycloheptyl-l- [4- (2H-1, 2, 3- 1 r iazol-2-yl ) benzyl ] -3-
(2,4, 6-trimethylphenyl) urea
mp : 157-158°C
IR (KBr) : 3311, 2924, 2856, 1626, 1512, 1255, 955,
35 847 cm"^
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15
25
30
35
- 183 -
NMR (CDCI3, 5) : 1 40-2 10 n 9r , .
J J-.^u z.iu (12H, m) , 2.04 (6H, s)
2-21 (3H, sj, 4.25-4.45 (IH, m) , 4.57 (2H s) '
^•82 (2H, s), 8.04-8.14 (2H, m)
APCI-MASS (m/z) : 432 (M+H+)
(31) ;-J^^o^eptyl-i-H-(4-.ethylplperaz.n-l^
(^,4, b-triniethylphenyl) urea
IR (KBr, : 3390, 3335, 2925, 2855. 2795, 2360, 1645
1610, 1515 cm"l
2.20 ,6H, s,, 2.4-2.5 ,4H, , 3.05-3.15 ,4H, „, ,
(2H, d, J.8.5H2), 7.16 (2H, d, J.8.5H2), 7 34
(IH, br s)
APCI-MASS (m/2) : 463 (M+H+}
(32) ^-^y-loheptyl-l-M-(4-methylsulfonylaminophenyl)-
'^^^'^'^-^-^2,4,6-trxmethylphenyl)urea
'^^^^ ■ ''''' 3340, 2975, 2925, 2860, 1640,
1500 cm-1
NMR (DMSO-d„ 6) : x.3-1.9 (12H, , 2 . 08 3)
2-20 (3H, s), 3.01 (3H, s), 4.1-4.3 (IH, n.) , 4 53
(2H, 3), 6.83 (2H, s), 7.27 (2H, d, J=8.4Hz)
7.37 (2H, d, J=8.4Hz), 7.53 (IH, br 3), 7.55-7 7
(4H, m) , 9.82 (IH, s)
APCI-MASS (m/2) : 534 (M+.H+)
(33) l-Cycloheptyl-l-f4-[2-(l-trityl-lH-tetrazol-5-
yl ) phenyl ] benzyl ] -3- (2, 4, 6- trrmethylphenyl , urea
IR (KBr) : 3407, 3058, 3026, 2924, 2856, 1647, I6O8
14 93 cm-1
NMR (DMSO-d^, 6) • 1 4-1 r nou
^ ' • (12H, m) , 2.04 (6H, s)
2-20 {3H, 3), 4.05-4.25 (IH, m) , 4.48 (2F 3) '
6-83 (2H, s), 7.04 (2H, d, J=7.9Hz), 7.23 (2H,' d.
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J=7.9Hz), 7.5-7.8 (5H, m)
FAB-MASS (m/z) : 751 {M+H"^)
(34) 1-Cycloheptyl-l- [4- (N-benzoylsul fainoyl ) benzyl ] -3-
5 (2 , 4 , 6-trimethylphenyl ) urea
IR (KBr) : 3415, 3361, 2924, 2858, 1632, 1593,
1549 cm~l
NMR (DMSO-dg, 5) : 1.4-2.0 (12K, m) , 2.07 (6H, s),
2.20 (3H, s), 4.1-4.3 (IH, m) , 4.51 (2H, s), 6.81
10 (2H, s), 7.2-7.4 {5H, m) , 7.53 (IH, br s), 7.76
(2H, d, J=8.0Hz), 7.88 (2H, d, J=8.0Hz)
APCI-MASS (m/z) : 548 (M+H"^)
(35) 1-Cycloheptyl-l- [4- (N-phenylsul fonylcarbamoyl) benzyl ] -
15 3- ( 2 , 4 , 6-trimethylphenyl ) urea
IR (KBr) : 3380, 3290, 3055, 2920, 2855-, 1690, 1625,
1610, 1505 cm"l
NMR (DMSO-dg, 5) : 1.3-1.8 (12H, m) , 2.07 (6H, s),
2.21 (3H, s), 4.1-4.25 (IH, m) , 4.53 (2H, s),
20 6.83 (2H, s), 7.38 (2H, d, J=8.2Hz), 7.65-7.8
(4H, m) , 7.82 (2H, d, J=8.2Hz), 8.00 (2H, d,
J=6 . 7Hz)
APCI-MASS (m/z) : 548 (M+H"^)
25 (36) 1-Cycloheptyl-l- [4- (3-pyridylmethyl)benzyl] -3- (2, 4, 6-
trimethylphenyl ) urea
IR (KBr) : 3412, 3304, 3028, 2920, 2854, 1626,
1502 cm"^
NMR (CDCI3, 5) : 1.4-2.1 (12H, m) , 1.95 (6H, s), 2.21
30 (3H, s), 3.98 (2H, s), 4.35-4.55 (IH, m) , 4.48
(2H, s) , 5.42 (IH, s), 6.79 {2H, s), 7.19 (2K, d,
J=7.7Hz), 7.15-7.25 (IH, m) , 7.35 (2H, d,
J=7.7Hz), 7.4-7.5 (IH, m) , 8.4-8.5 (2H, m)
APCI-MASS (m/z) : 456 (M+H"^)
35
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(37; l-Cycloheptyl-l-M-(.-pyridyl...ethyl, benzyl 1-3- (2 4 6-
trimethylphenyl ) urea ' ' '
IR ,KBr, : 3408, 330., 302., 2922, 2a56, i632, 1605
1512 cm-1
NMR (CDCI3, 5) : 1.4-2.1 ( i ^, 7 gc ,
s), 3.96 (2K, s' 4 / -,
' " "-^5-4.5 (IH, ra) , 4.48
3), 5.42 (IH, s;, 6.79 (2H, s), 7.C9 (
dd, J=6.0, 1.6Hz), 7.20 (2H, d, J=8.1F.) 7 37
^' 8.49 (2K, ad, J=6.0, ^SHz)
APCI-MASS (m/z) : 456 (M-.H^)
(38) 1-Cycloheptyl-l- (3-be.nzyibenzyl) -3- (2, 4, 6-
trimethylphe.nyl) urea
'■ ^223, 3025, 2922, P854 ^ f,o - ^c^n. -1
■1^ NMR (CDCI3, 5) ■ 1 c '
3 ) ■ 1.- 2.0 (.2.^., n), 1.95 (6H, s), 2.21
(3H, s), 3.97 (2H, s), 4.46 (2H, s), 4.3-4.5 (^K
5.42 (l.H, s), 6.73 (2.H, s), 7.1-7.35 (9^ V^'
APCI-MASS (m/z) : 455 (M+H+)
10
20
25
'39, i-Cycloheptyl-l-(.-,pyrazol-l-yl„ethyl|benzylJ-3-
(2,4, 6-trimethylphenyl) urea
ir.p : ISO-lSl-'C
(KBr) : 3307, 2922, 2856, 1628, 1506, IP50
750 cin~I
NMR (CDCI3, 5) : 1 38-2 05 1 ^ '>u
3 ^-^^ ^-^^ (12H, m) , 1.97 s)
2.21 (3H, s), 4.30-4.45 (IH, m) , 4.49 (2P s) '
^-^^ ^-28 (IK, dd, J=2:o,
2.0hz;, 6.79 (2H, s), 7.15-7.28 (2H, ...) , 7 32-
^-^2 (3.H, m), 7.55 (IH, d, J=2.0Hz)
3U APCI-MASS (m/z) : 44 5 (M+H+)
(^0) l-Cycloheptyl-i-r4-(xmxdazol-l-yim.erhyl)benzvl-3-
(2, 4 , 6- trimethylphenyl ) urea
IH (KBr) : 3329 (br) , 2924, 2856, 1637, 1504, ^.3.
849, 735 cm-i
35
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NMR (CDCI3, 5) : 1.35-2.05 (12H, m) , 1.99 (6H, s),
2.21 {3H, s), 4.25-4.45 (IH, m) , 4.51 (2H, s),
5.12 {2H, s), 5.40 (IH, s), 6.80 (2K, s), 6.89
(IH, s), 7.10 (IH, s), 7.13-7.23 (2H, m) , 7.35-
5 7.45 (2H, m) , 7. 61 (IH, s)
APCI-MASS (m/z) : 445 (M+H"^)
(41) 1-Cycloheptyl-l- [ ( 6-hydroxy-2 , 5, 7, 8-tetramethyl-
chroman-2-yl) methyl] -3- (2, 4, 6-triinethylphenyl ) urea
10 IR (KBr) : 3313, 2924, 2858, 1740, 1643, 1610,
1510 cm"l
NMR (DMSO-dg, 6) : 1.15 (3H, s), 1.3-2.1 (16H, m) ,
2.55-2.65 (IH, m) , 1.92 (3H, s), 1.99 (3H, s),
2.02 (6H, s), 2.03 (3H, s), 2.21 (3H, s), 3.53
15 (2H, br s), 6.83 (2H, s), 7.44 (IH, br s)
APCI-MASS (m/z) : 493 (M+H"^)
(42) 1-Cycloheptyl-l- [4- [N- {3, 5-di-tert-butyl-4-
hydroxyphenyl) carbamoyl ] benzyl ] -3- (2,4,6-
20 trimethylphenyl ) urea
IR (KBr) : 3639, 3417, 3321, 2951, 2924, 2860, 1643,
1610, 1502 cm~l
NMR (DMSO-dg, 5) : 1.39 (18H, s), 1.4-1.9 {12H, m) ,
2.10 (6H, s), 2.21 (3H, s), 4.1-4.3 (IH, m) , 4.57
25 (2H, s), 6.78 (IH, s), 6.85 (2H, s), 7.41 (2H, d,
J=8.3Hz), 7.90 (2H, d, J=8.3Hz), 7.44 (2H, s),
7.59 (IH, br s), 9.87 (IH, br s)
APCI-MASS (m/z) : 612 (M+H"^)
30 (43) 1-Cycloheptyl-l- [4- [N- (4-fluorophenyl ) carba.moyl i -
benzyl] -3- (2, 4, 6-trimethylphenyl ) urea
IR (KBr) : 3280, 2926, 2856, 1643, 1610, 1549,
1508 cm"l
NMR (DMSO-dg, 6) : 1.4-1.9 (12H, m) , 2.11 (6H, s),
^5 2.21 (3H, s), 4.1-4.3 (IH, m) , 4.57 (2H, s), 6.85
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(2H, s), 7.15-7.3 (2H, n.) , 7.43 (2H, d, J=8.2H^)
-7.64 (IH, br s), 7.75-7.85 (2H, :n) , 7.90 (2H, d '
J=8.2Hz), 10.22 (IH, s)
APCI-MASS (m/z) : 502 (M+H+)
5
(44) 1-Cycloheptyl-l- [4- [N- ( 4 -f luorophenyl ) -n-
n.ethyicarba.oyl,benzyl, -3- (2, 4 , 6-....ethylphenyI) urea
"^/^"^^ ^^2^' ^^23, 2860, 1638, 1606 c"!
•• ^-^-^-B (I2H, 2.01 C6H, 3),
2-20 (3H, s), 3.30 (3H, s), 4.0-4.2 (IH, xn) , 4.42
(2H, s), 6.82 (2H, s), 7.05-7.3 (8H, m) , 7.47
(IH, br s)
APCI-MASS (m/z) : 516 (M+H+)
15
20
25
30
(45) 1-Cycloheptyl-l- f 4- [ (2, 4 -dioxothiazolidin-5-
yl ) methyl ] benzyl ] - 3- (2 , 4 , 6-trxn.ethylphenyl ) urea
IH (KBr) : 2931, 2858, 2765, 1753, 1709, 1689, 1606,
1632, 1564, 1535, 1502, 1481 cra'^
NMR (DMSO-d„ 6) : 1.4-2.1 (12H, .),2.05 (6H, s)
2.20 (3H, s), 3.0-3.2 (IH, .) , 3.3-3.45 (IH, ,
4.0-4.2 (IH, .), 4.47 (2H, s), 4.85-5.0 (IH,
0-82 (2H, s), 7.19 (2H, d, J=8.2Hz), 7.25 (2- d
J=8.2Hz), 7.44 (IH, br s), 12.3 (IH, br)
APCI-MASS (m/z) : 494 (M+H+)
(46) l-Cycloheptyl-l-[4-[(2,4-dioxothiazolidin-5-
ylidene)n.ethyl]benzyl]-3-(2,4,6-trixnethylphenyl)urea
IR (KBr) : 3410, 3122, 2924, 2958, 2758, 1743, 1707,
1603, 1504 cm--
NMR (DMSO-dg, 6) : 1.4-1.9 (12H, n.) , 2.08 ( 6H s)
2.21 (3H, 3), 4.1-4.3 (IH, ..) , 4.54 (2H, s), 6.84
(2H, 3), 7.44 (2H, d, J=8.3Hz), 7.56 (2H, d
J=8.3Hz), 7.61 (IH, br s), 7.77 (IH, s), l/fiO
(IH, br)
35 APCI-MASS (m/z) : 492 (M+H+)
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(47) 1-Cycloheptyl-l- [4- (2-cyanophenyl ) benzyl] -3- (2, 4, 6-
rrimethylphenyl ) urea
IP. (KBr) : 3410, 3330, 2925, 2855, 2225, 1640, 1610,
1500 cm"-
5 NMR (CDCI3, o) : i.5-1.8 (12H, ir.) , 2.02 (cH, sj, 2.21
(3H, s), 4.35-4.55 {IK, m) , 4.58 (2H, s), 5.4 9
(IH, s), 6.30 (2H, s), 7.4-7.8 (8H,
APCI-MASS (m/z) : 466 (M+H"*" )
10 Example 2 3
The following compounds were obrained according to a
similar manner to that of Exam.ple 7, 8, 9, 10, 13, 14, 15,
16 or 17 .
15 (1) 1-Cycloheptyl-l- [4- ( 4 ' -chlorophenoxy) benzyl ] -3- [2 , 4-
bis (methyl thio) -6-methylpyridin-3-yl ] urea
IR (KBr) : 3371, 2924, 2856, 1662, 1589, 1564, 1506,
14 85 cm"-
NMR (DMSO-dg, 5) : 1.35-1.9 (12H, m) , 2.39 (6H, s),
20 2.44 (3H, s), 4.0-4.2 (IH, m) , -4.46 (2H, s), 6.86
(IK, s), 6.95-7.1 (4H, m) , 7.35-7.5 (4K, m) , 7.84
(IK, br s)
APCI-MASS (m/z) : 556 (M+H"^)
25 (2) 1-Cycloheptyl-l- [4- (4-fluorophenoxy; benzyl ] -3- [2, 4-
bis (methyl thio ) - 6-methylpyridin-3-yl ] urea
IR (KBr) : 3313, 2955, 2924, 2872, 1655, 1564,
14 97 cm~-
NMR (DMSO-dg, 6) : 1.4-1.9 {8H, m) , 2.39 (6K, s),
30 2.44 (3K, s), 4.3-4.5 (IH, m) , 4.47 (2K, s), 6.86
(IH, s), 6.9-7.1 (4K, m) , 7.15-7.35 (4H, n) , 7.S7
(IH, £)
APCI-MASS (m/z) : 512 (M+K")
35
(3) 1-Cycloheptyl-l- ( 3-phenoxybenzyl ) -3- [2, 4-
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bis(methylthio)-6-methylpyridin-3-yl]ur-ea
IR (K3r) : 3294, 2924, 2954, 174C, 1635, 1562,
14S3 ci?r'-
NMR (DMSO-d„ o; : 1.3-2.0 (12H, n) , 2.32 (6F,
2-43 (3H, s;, 4.0-4.2 (IH, m)", 4.47 (2H, s) / 6 83
(IH, s), 6.9-7.45 (9H, m) , 7.84 ( i s
APCI-MJ^S (m/z) : 522
35
(4) ^-Cycloheptyl-l-[3-(4-fluorophenoxv)benzyl]-3-[2 4-
bis(methylthio)-6-methylpvridin-3-yl]ur-ea
IR (KBr) : 3332, 3066, 2926, 2856, 1664, 1608, 1564
1497
N-MR (CDCI3, 5) : 1.45-2.05 a2K, xn) , 2.34 (3H, s)
2-45 (6H, s), 4.15-4.4 (IH, n) , 4.54 (2K, s)
5.46 (IK, s), 6.58 (IH, s), 6.85-7.4 (8H,' .t.) '
(5) 1- (4-Dixnethyla.minobenzyl) -1- f 3- (pyrazol-3-yl ) benzyl 1 -
3 (2, 4, 6-trif luorophenyl) urea
IR (KBr) : 2600-3650 (br) , 1635, 1614, 1522, 1448,
13 52 cm -
(DMSO-dg, 5) : 2.83 (6H, s), 4.38 (2H, s), ...7
(2H, s), 6.55-6.77 (3H, n) , 7.08-7.83 (9F, r.)
8-39 (IH, s), 12. 89, 13.33 (::otal IH, eacr fal)'
APCI-MASS (m/z) : 4 80 (M+H+)
(6) 1- (2, 3, 5, 6-Tetrahydro-4H-pyran-4-yl) -1- [4- (4.
f luorophenoxy) benzyl] -3- [2, 4-bis (methylthio) -6-
methylpyridin-3-yl ] urea
IR (KBr) : 3294, 3064, 2956, 2926, 2848, 1655. 156.,
1497 cm~I
NMR (DMSO-d„ 5) : 1.55-1.85 (4H, .m) , 2.40 (cH, s),
2.45 (3H, s), 3.3-3.5 (2K, m) , 3.8-3.9 (2H
4.1-4.3 (IH, m), 4.51 (2H, s), 6.87 (ih, si/^g-
■7.4 (8H, m) , 7.98 (IH, br s)
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(7) 1- (2-Phenylethyl ) -1- [4- ( 4-fluorophenoxy) benzyl] -3-
[2, 4-bis (methylthio ) - 6-methylpyridin- 3-yl ] urea
IR (KBr) : 3294, 3062, 3026, 2924, 1655, 1562,
14 97 cm"l
5 NMR (CDCI3, 5) : 2.40 {3H, s), 2.48 (3H, s), 2.51
(3H, s), 3.01 (2H, t, J=7.8Hz), 3.61 (2H, t,
J=7.8Hz), 4.43 (2H, s), 5.65 (IH, br s), 6.64
(IH, s), 6.9-7.1 (6H, m) , 7.2-7.35 (7H, m)
APCI-MASS (m/z) : 54 8 (M+H"^)
10
{ 8 ) 1- (2-Ethoxyethyl ) -1- [4- {4-fluorophenoxy) benzyl ] -3-
[2, 4 -bis (methylthio) - 6-methylpyridin- 3-yl ] urea
IR (KBr) : 3298, 3063, 2976, 2926, 2881, 2856, 1664,
1562, 1495 cm"l
15 NMR (DMSO-dg, 5) : 1.12 (3H, t, J=6.9Hz), 2.40 (6H,
s), 2.45 (3H, s), 3.46 (2H, q, J=6.9Hz), 3.4-3.65
(4H, m) , 4.54 {2H, s), 6.87 (IH, s), 6.93-7.4
( 8H, m) , 7.9 (IH, br s)
APCI-MASS (m/z) : 516 (M+H"^)
20
(9) 1-Benzyl-l- ( 3-phenoxybenzyl ) -3- [2, 4-bis (methylthio) -6-
me thy Ipyri din- 3-yl ] urea
IR (KBr) : 3404, 3032, 2997, 2922, 1668, 1610, 1562,
1500, 1452 cm~^
25 NMR (DMSO-dg, 5) : 2.35 (6H, s), 2.43 (3H, s), 4.44
(2H, s), 4.47 (2H, s), 6.86 (IH, s), 6.9-7.45
(14H, m) , 8 .24 (IH, br s)
APCI-MASS (m/z) : 516 (M+H"^)
30 (10) 1-Benzyl-l- [3- (4-fluorophenoxy) benzyl] -3- [2, 4-
bis (methylthio) -6-methylpyridin- 3-yl ] urea
IR (KBr) : 3298, 3062, 3028, 2922, 1662, 1564,
14 98 cm"l
NMR (CDCI3, 6) : 2.36 (3H, s), 2.46 (6H, s), 4.61
35 (2H, s), 4.62 (2H, s), 5.66 (IH, s), 6.85-7.4
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- 191 -
(13H, m)
APCI-MASS (m/z) : 534 (M+H+)
(11) l-Cycloheptyl-l-[3-(pyrazol-3-yl)benzyl]-3-[2,4-
bis(methylthio)-6-methylpyridin-3-yl]urea
(KBD : 3211, 3061, 2924, 2856, 1643, 1564, 1531
1485 cm-1
NMR fDMSO-d„ 5) : 1.4-1.9 (12H, , 2.39 (6H, s)
2.45 (3H, s), 4.0-4.2 (IH, m) , 4.52 (2H, s), 6 6-
6.7 (IH, m), 6.86 (IH, s), 7.2-7.9 (6H, m) , 12 85
(IH, br s)
APCI-MASS (m/z) : 496 (M+H+)
(12) l-Benzyl-l-[3-(l-n.ethylpyrazol-3-yl)benzyl]-3-[2 4-
bis (methylthio) -6-methylpyriciin-3-yl] urea
mp : 165-166°C
IR (KBD : 3280, 2922, 1643, 1562, 1500, 1435 en."!
NMR (CDCI3, 5) : 2.36 (3H, s,, 2.46 (6H, s), 3.95
(3H, s), 4.66 (4H, s), 5.70 (IH, s), 6.57 (1k, a
J-2.3HZ), 6.61 (IH, s), 7.22-7.45 (8H, m) , 7.72-
7.80 (2H, m)
FAB-MASS (m/z) : 504 (M+H+)
(13) l-Benzyl-l-[3-(l-methylpyrazol-5-yl)benzyl]-3-[2,.-
bis (methylthio)-6-methylpyridin-3-yl]urea
IR (KBr) : 3280, 2922, 1649, 1562, 1500, 1431,
1390 cm"l
NMR (CDCI3, 5) : 2.35 (3H, s), 2.45 (3H, s), 2.46
(3H, s), 3.88 (3H, s), 4.64 (2H, s), 4.71 (2H
s), 5.70 (IH, s), 6.32 (IH, d, J=1.9Hz), 6.61'
(IH, s) , 7.20-7.55 (lOH, m)
FAB-MASS (m/z) : 504 (M+H+)
(14) l-Benzyl-l-[4-(l-methylpyrazol-3-yl)bGnzyl]-3-[2,4-
bis (inethylthio)-6-methylpyridin-3-yl]urea
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IR (KBr) : 3305, 2922, 1659, 1564, 1489, 1338,
1227 cm"-
NMR {CDCI3, 6) : 2.38 (3H, s), 2.47 (3K, s), 2.49
(3H, s), 3.96 (3H, s), 4.63 (4H, s), 5.71 (IH,
5 s), 6.54 (IH, d, J=2.3Hz), 6.62 (IH, s), 7.25-
7.47 (8H, m) , 7.75-7.85 (2H, m)
APCI-MASS (m/z) : 504 (M+H"^}
(15) 1 -Benzyl- 1- [4- ( 1 -me thylpyr azol- 5-yl ) benzyl ] -3- [2, 4-
10 bis (methylthio) -6-methylpyridin-3-yl ] urea
IR (KBr) : 3286, 2922, 1657, 1562, 1495, 1389 cm-^
NMR (CDCI3, 6) : 2.40 (3K, s), 2.47 (3H, s), 2.49
(3H, s), 3.90 (3H, s), 4.66 (2H, s), 4.69 {2K,
s), 5.71 (IH, s), 6.31 (IK, d, J=1.9Hz), 6.63
15 (IH, s), 7.25-7.51 (9H, m) , 7.52 (IH, d, J=1.9Kz)
APCI-MASS (m/z) : 504 (M+H''")
(16) 1-Benzyl-l- [4- (pyrazol-3-yl) benzyl ] -3- [2, 4-
bis (methylthio) - 6-methylpyridin-3-yl ] urea
20 mp : 150-152°C
IR (KBr) : 3400, 3215, 2922, 1649, 1560, 1487,
1228 cm~-
NMR (DMSO-dg, 5) : 2.4 4 (6H, s), 2.4 7 (3H, s), 4.4 6
(4H, s), 6.72 (IH, s), 6.90 (IH, s), 7. 22-7. 90
25 (lOH, m) , 8.30 (IH, s), 12.87, 13.27 (toral IK,
each br)
APCI-MASS (m/z) : 490 (M+H"^ )
(17) 1-Cycloheptyl-l- [4- (pyrazoi-3-yl ) benzyl ] -3- [2, 4-
30 bis (methylthio) - 6-methylpyridin- 3-yl ] urea
mp : 174-175 °C
IR (KBr) : 2690-3700 (br), 2924, 2856, 1637,
1564, 1484, 1340, 1207, 804 err " 1
NMR (DMSO-dg, 5) : 1.30-1.90 {12H, m) , 2.41 (5H, s),
35 2.45 (3H, s), 3.95-4.15 (IK, m) , 4.49 (2H, s),
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30
35
12.80, 13.19 (total IH, each br)
APCI-MASS (m/z) : 436 (Mt.H* )
na) ^-'^-«-tho=<,benzyl,-i-,3-,pyrazol-3-,i,,,„,,„.3.j, .
b.s<.ethylthio,-6-„ethylpyridin-3-yl,.,ea
mp : 170-1 73 °C
<KBr, : 33S,, 3250, 3101, ...0, 1.... 1362, 1.33
1223 cm-l '
"'~r:' •■ <3H. s,., 3.,3
<3H. s>. ^.41 ,2H, s,, (2H, s,, 6.67 ,1H, br
—.03 ,3H. ..i3-..,o ,,,, 3,^;
(IH, s), 12.89, 13.30 (total IH, each br)
APCl-MASS (m/z) : 520 (H-H* ]
(19) ^-<^-^l"orobenzyl)-i-,3-(pyrazol-3-yl,benzylJ-3-[2
bxs,methylthio)-6-Methylpyridin-3-yljurea
nip : lee-ies^c
IR (KBr, : 3390, 3257, 2920, 1653, 1562, l.e9
1227 cm-1
-.2 ..H, s., 2... 3., ....
(2H, s), 4.49 (2H, 3,, 6.66 (IH, d, J=2.0-.z)
6-90 (IH, s), 7.12-7.45 (6H, , 7.60-7.90
'-'^ ^3.30 (total IH, each'
APCI-MASS (m/z) : 5O8 (M+H+)
(20) -^--i-thyla.lnobenzyl)-l-f3-(p,...ol-
3- [2, 4-ba3 (methylthio) -6-nethylpyridin-3-yl ] urea
mp : 185-188°C
IR (KBr) : 3236 i - -3 ■:! 1--,.-,
-^^36, 2922, lo33, 1612, 1524, 1487, 1338
1219 cm-1
NMR (DMSO-d^, 5) • 2 49 /'u
6' 6) . 2.42 (cH, 3), 2.47 (3H, s), 2.89
3 , 4.35 (2H, .r 3), 4.42 (2H, br s), 6.60-
(3H, m), 6.90 (IK, 3), 7.10-7.90 (7H, m) ,
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8.23 (IH, s), 12.89, 13.30 (total IH, each br)
APCI-MASS (m/z) : 533 (M+H"*")
(21 ) 1-Benzyl-l- [4- ( l-methylpyrazol-4-yl ) benzyl] -3- [2, 4-
5 bis (methylthio) -6-methylpyridin-3-yl ] urea
mp : 224-225°C
IR (KBr) : 3217, 2922, 1655, 1566, 1498, 1456, 1228,
806 cm"^
NMR (DMSO-dg, 6) : 2.43 (6H, s), 2.47 (3H, s), 3.86
10 (3H, s), 4.30-4.50 (4H, m) , 6.90 (IH, s), 7.20-
7.40 (7H, m) , 7.50-7.60 (2H, m) , 7.86 (IH, s),
8.13 (IH, s), 8.28 (IH, s)
APCI-MASS (m/z) : 504 (M+H"^)
15 (22) 1-Cycloheptyl-l- [4- (l-methylpyrazol-4-yl) benzyl] -3-
[2, 4 -bis (methylthio) -6-methylpyridin-3-yl ] urea
mp : 24 7-24 8°C
IR (KBr) : 3188, 2922, 2854, 1641, 1564, 1491,
1213 cm"l
20 NMR (DMSO-dg, 6) : 1.30-1.90 (12H, m) , 2.40 (6H, s),
2.45 (3H, s), 3.85 (3H, s), 3.90-4.15 (IH, m) ,
4.45 (2H, s), 6.86 (IH, s), 7.28-7.38 (2H, ir.) ,
7.43-7.54 (2H, m) , 7.83 (IH, s), 7.85 (IH, br s),
8.10 (IH, s)
25 APCI-MASS (m/z) : 510 (M+H"^)
(23) 1-Benzyl-l- [3- ( imidazol-4 -yl ) benzyl] -3- [2, 4-
bis (methylthio ) -6-methylpyridin-3-yl ] urea
mp : 134-136°C
30 IR (KBr): 2690-3700 (br), 1637, 1562, 1490, 1228 cm'^
NMR (DMSO-dg, 5) : 2.43 {6H, s), 2.47 (3H, s), 4.47
(4H, s), 6.90 (IH, s), 7.10-7.75 (IIH, m) , 8.28
(IH, s), 12.17, 12.55 (total IH, each br)
APCI-MASS (m/z) : 490 (M+H"^)
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(2.) ^-Benzyl-i-r3-(2-n.ethyl-2H-tetrazol-5-yl,benzyl]-3-
[2,4-bis(methylthio)-6-niethylpyridin-3-yl]urea
IR (KBr) : 3290, 2922, 1655, 1562, 1,93, 1227, 970
806 cm"l
NMR (CDCl^, 5) • 2 39 r3H <ri o ^
^ ' ■ "^--^^ s), 2.47 (3H, s), 2 48
s), 4.40 (3H, s), 4.67 (2H, s), 4.72 (2H,
5.72 (IH, s), 6.62 (IH, s), 7.25-7.58 (7H
m), 8.01-8.18 (2H, m)
APCI-MASS (m/z) : 506 (M+H+)
(25) 1-Cycloheptyl-l- [4- [ (2, 4-dioxothiazolidin-5-
yl)inethyl]benzyl]-3-[2,4-bis(methylthio)-6-
niethylpyridin-3-yl] urea
IR (KBr) : 2924, 2860, 2769, 1753, 1701, 1603,
1506
NMR (DMSO-d^, 5)- l4-iQn9H , ^
6' -L-'^ 1-9 (12H, m) , 2.40 (6H, s)
2-45 (3H, s), 3.07 (IH, dd, J=14.0, 9.4H^) 3 35
(IH, dd, J=14.0, 4.3HZ), 3.95-4.15 (IH, m) ,' 4.45
20 '-'^ ^=5-^' ^-^Hz), 6.86 (IH,
s), 7.17 (2H, d, J=8.1HZ), 7.30 (2H, d, J=8.1Hz),
7-86 (IH, br s) , 12. 04 (IH, br)
APCI-MASS (m/z) : 559 {M+H+)
35
(26) 1-Cycloheptyl-l- [4- [ (2, 4-dioxothiazolidin-5-
ylidene)inethyl]benzyl]-3-[2,4-bis(methylthio)-6-
inethylpyridin-3-yl j urea
IR (KBr) : 3406, 3124, 2926, 2856, 2765, 1757, 1711,
1635, 1599, 1487 cm~^
NMR (DMSO-d^, 6) • 1 3-1 q Mou
6' • 1-3 1.9 (12H, m) , 2.40 (6H, s),
2-45 (3H, s), 4.0-4.2 (IH, m) , 4.52 (2H, br si
6.86 (IH, s), 7.48 (2H, d, J=8.6Hz), 7.54 (2F 'd
J-8.6HZ), 7.77 (IH, s), 7.96 (IH, br s), 19 59
(IH, br)
APCI-MASS (m/z) : 557 (M+H+)
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(27) l-3enzyl-l- [4- ( 4-fluorophenoxy) benzyl ] -3- (2, 4, 6-
trimethylpyridin-3-yl ) urea
IR (KBr) : 3294, 3030, 2922, 1632, 1605, 1498 crrr^
NMR (DMSO-dg, 5) : 2.08 (3H, s), 2.26 (3K, s), 2.35
5 (3H, s), 4.52 (2H, s), 4.56 (2K, s), 6.95-7.45
(14H, m) , 8 . 02 (IH, br s]
APCI-MASS (m/z) : 476 (M+K"^)
(28) 1-Cyclohexyl-l- [4- ( 4-fluorophenoxy) benzyl] -3- (2, 4, 6-
10 trimethylpyridin-3-yl) urea
IR (KBr) : 3406, 3313, 2929, 2856, 1714, 1632, 1605,
1572, 1495 cm~^
NMR (DMSO-dg, 5) : 1.0-1.9 (lOH, m) , 2.07 (3H, s),
2.24 (3H, s), 2.34 (3H, s), 3.95-4.15 (IK, m) ,
15 4.51 (2H, s), 6.95-7.4 (&H, m) , 7.70 (IH, s)
APCI-MASS (rn/z) : 462 (M+H"^)
(29) 1-Cycloheptyl-l- [4- ( 4-broinophenoxy ) benzyl ] -3- (2,4,6-
tr imethylpyridin-3-yl ) urea
20 IR (KBr) : 3310, 1632, 1504, 1483, 1238 ct"^
NMR (CDCi3, 5) : 1.38-2.05 (12H, m) , 2.04 (3H, s),
2.20 (3H, s), 2.42 (3H, s), 4.30-4.50 (IH, m) ,
4.50 (2H, s), 5.49 (IH, s), 6.82 (IK, s), 6.85-
6.93 (2K, m) , 6.98-7.08 {2K, m) , 7.32-7.45 (4K,
25 m)
APCI-MASS (m/z) : 536, 538 (M+K"^)
( 30 ) 1-Benzyl-l- [3- (pyrazol-3-yl) benzyl ] -3- ( 2 , 4 , 6-
triinethylpyridin-3-yl) urea
30 IR (KBr) : 3236, 2924, 1645, 1564, 1493 cm"-
NMR (DMSO-dg, 5) : 2.10 (3H, s) , 2.2 8 {3H, s), 2.3 5
(3H, s), 4.59 (4H, s), 6.6-6.7 (IH, ir.; , 6.94 (IK
s), 7.2-7.8 (lOH, m) , 3.0" (IK, br s), 12.89 (IK
br)
3 5 APCI-MASS (m/z) : 42 6 (M+H"^)
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(31) l-Cycloheptyl-l-[3-(l-tritylpyrazol-3-yl)benzylJ-3-
(2, 4, 6-trimethylpyridin-3-yl) urea
IR (KBr) : 3404, 3313, 3059, 3028, 2924, 2856, 1720,
1650, 1605, 1500, 1481 cm-^
NMR (DMSO-dg, 6) : 1.4-1.9 (12H, xn), 1.96 (3H, s),
2.19 (3H, s), 2.33 (3H, s), 4.1-4.3 (IH, m) , 4.54
(2H, s), 6.71 (IH, d, J=2.5Hz), 6.85 (IK, s),
7.1-7.8 (20H, m)
FAB-MASS (m/z) : 674 (M+H+)
(32) l-Benzyl-l-[4-(4-fluorophenoxy)benzyl]-3-[4,6-
bis (methyl thio)-2-methylpyridin-5-yl] urea
IR (KBr) : 3275, 3062, 3030, 2926^ 1637, 1535,
1479 cm"i
NMR (DMSO-dg, 6) : 2.46 ( 6H, s), 2.58 (3H, s), 4.44
(2H, s), 4.48 (2H, s), 6.95-7.4 (13H, m) , 8 39
(IH, br s)
APCI-MASS (m/z) : 535 (M+H+)
(33) l-Cycloheptyl-l-[4-(4-bromophenoxy)benzyl]-3-[4,6-
bis (i^ethylthio)-2-methylpyrimidin-5-yl]urea
mp : 173-175°C
IR (KBr) : 3375, 2926, 2852, 1668, 1583, 1479, 1238,
810 cm"l
25 NMR (CDCI3, 6) : 1.38-2.10 (12H, m) , 2.48 (6H, s),
2.59 (3H, s), 4.20-4.42 (IH, m) , 4.54 (2H, s),
5.40 (IK, s), 6.85-6.93 (2H, m) , 7.00-7.10 (2H,
m) , 7.34-7.50 (4H, m)
APCI-MASS (m/z) : 601, 603 (M+H+)
(34) 1-Benzyl-l- [ 3- ( 4-f luorophenoxy ) benzyl ] -3- [ 4 , 6-
bis (methylthio) -2-methylpyrimidin-5-yl ] urea
IR (KBr) : 3271, 3059, 3030, 2926, 2789, 2735, 2605,
1639, 1585, 1533, 1508 cm~^-
NMR (CDCI3, 5) : 2.46 (6H, s), 2.58 (3H, s), 4.61
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(4H, br s), 5.58 {IH, s), 6.8-7.4 (13H, m)
APCI-MASS im/z) : 535 {M+H+)
(35) 1-Cycloheptyl-l- [3- {pyra20l-3-yl) benzyl ] -3- [ 4 , 6-
bis (methyl thio) -2-methylpyrimidin-5-yl ] urea
mp : 164-165''C
IR (KBr) : 3194, 2926, 2856, 1633, 1518, 1419, 1296,
812 cm~l
NMR (DMSO-dg, 5) : 1.30-1.90 (12H, m) , 2.43 (6H, s),
2.57 (3H, s), 3.95-4.15 (IH, m) , 4.53 (2H, s),
6.65 (IH, s), 7.15-7.90 (5H, m) , 8.07 (IH, s),
12.86, 13.30 (total IH, each br)
APCI-MASS (m/z) : 4 97 (M+H"^)
15 (36) 1-Benzyl-l- [3- (pyrazol-3-yl)benzyl] -3- [4, 6-
bis (methylthio) -2-methylpyrimidin-5-yl ] urea
mp : 212-213°C
IR (KBr) : 3388, 3265, 2924, 1653, 1524, 1487, 1390,
1356, 1298, 1228 cm~^
20 NMR (DMSO-dg, 5) : 2.46 (6H, s), 2.58 (3H, s), 4.50
(4H, s), 6.60-6.70 (IH, m) , 7.15-7.85 (lOH, m) ,
8.45 (IH, s), 12.89, 13.32 (total IH, each br s)
APCI-MASS (m/z) : 491 (M+H"^ )
25 (37) 1-Benzyl-l- [4- (4 ' -fluorophenoxy) benzyl] -3- [2, 4-
dimethoxy-6-methylpyridin-3-yl ] urea
IR (KBr) : 3394, 3315, 3062, 2945, 2858, 1660, 1597,
1497 cm~l
NMR (DMSO-dg, 5) : 1.99 (3H, s), 3.80 (3H, s), 3.81
30 (3H, s), 4.41 (2K, s), 4.45 (2H, s), 6.67 (IH,
s), 6.95-7.45 (13H, m)
APCI-MASS (m/z) : 502 (M+H"^)
(38) 1-Cycloheptyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- [2, 4-
dimethoxy- 6-methylpyridin- 3-yl ] urea
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IR (KBr) : 3379, 220.1, 3055, 2926, 2856, 1651, 1557,
1502 cm~-
NMR (DMSO-dg, 5) : 1.3- 1.9 ( 12H, -1, 2.35 (3H, s),
3.75 (3H, s,, 5.76 {6H, s) , 4.0-4.2 (IH, , ^ . 5C
^ (2H, s), 5.55 (IH, s;, c..^-e.iE>^ (IK, m) , 7.1-7.8
{5H, m) , 12 . 65 (IH, br s)
(39) l-3enzyl-l- [3- (l-trityipyrazol-3-yl) benzyl] -3- (2,4-
dime thoxy-6-met by Ipyridin- 3 -yi) urea
IR (KBr) : 3990, 5066, 3032, 2990, 2933, 1678, 1537,
1512, 1497 cm"^
NMR (DMSO-d^, 5) : 2.36 (3H, s), 3.72 (3H, sj, 3.74
(3H, s;, 4.4 6 (4H, br s), 6.64 (IH, s), 6.73 (IH,
'^i J=2.5Hz), 7.1-7.7 (2 4K, rr.)
(40) 1- (4-Fluorobenzyl) -l-[3- (l-tritylpyrazoi-3-yl) be.nzvl ] -
3- (2, 4, 6-trif luorophenvl) urea
20
IR (KBr) : 3294, 1637, 1608, 1519, 1446, 1225 cm"-
NMR (CDCI3, 5) : 4.58 (2H, s), 4.60 (2H, s), 5.75
(IK, s;, 6.54 (IH, d, J=2.5H2j, 6.57-7.10 (6H,
m) , -^.13-7.43 (18H, .-n; , 7.65-7.80 (2H, m)
(41) 1-Cyclohepryl-l- ( 4 -phenylbenzyl ) -3- (2, 4, 6-
25 tirime L;hylpyridin-3-yl ) urea
IR (K3r) : 3402, 3028, 2924, 2854, 1738, 1660, 1603,
1566, 1493 cm~-
NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 2.09 {3H, s) ,
2.27 (3K, s), 2.34 (3H, s), 4.05-4.25 (IH, m) ,
^—5 (2H, s), 6.93 (IH, s), 7.3-7.8 ( 9K, m)
APCI-MASS (m/z) : 442 (M+H+)
Example "4
The following coir.pounds were obtainea according to a
35
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similar manner to that of Example 6, 12 or 21.
(1 ) 1-Cycloheptyl-l- [4- (pyrazol-4-yl ) benzyl ] -3- (2,4,6-
trimethylphenyl ) urea
5 IR (KBr) : 3184, 2926, 2856, 1630, 1650, 1510 cm~^
NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 2.09 (6H, s),
2.21 (3H, s), 4.05-4.25 (IH, m) , 4.48 (2H, s),
6.83 (2H, s), 7.28 (2H, d, J=8.2Hz), 7.50 (IH, br
s), 7.56 (2H, d, J=8.2Hz), 7.87 (2H, s)
10
(2) 1-Cycloheptyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- [2, 4-
dimethoxy-6-methylpyridin-3-yl ) urea
IR (KBr) : 3406, 3228, 3062, 3026, 2974, 1676, 1653,
1597, 1508 cm"l
NMR (DMSO-dg, 6) : 2.37 (3H, s), 3.79 (3H, s), 3.80
(3H, s), 4.47 (4H, s) , 6.65 (IH, d, J=2.7Hz),
6.66 (IH, s), 7.2-7.5 (7H, m) , 7.65-7.8 (4H, m)
APCI-MASS (m/z) : 458 (M+H"^)
( 3 ) 1-Cycloheptyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- (2, 4, 6-
trimethylpyridin-3-yl ) urea
IR (KBr) : 3400, 3224, 3055, 2929, 2856, 1714, 1633,
1568, 1500 cm~^
NMR (DMSO-dg, 5) : 1.4-1.9 (12H, m) , 2.09 (3K, s),
2.26 {3H, s), 2.34 (3H, s), 4.05-4.25 (IH, m) ,
4.56 (2H, s), 6.6-6.7 (IH, m) , 6.91 (IH, s), 7.2-
7.5 (2H, m) , 7.6-7.9 (3H, m) , 12.85 ( IH, br s)
APCI-MASS (m/z) : 432 (M+H"^)
( 4 ) 1- (4-Fluorobenzyl) -1- [3- (pyrazol-3-yl ) benzyl ] -3-
(2, 4, 6-trif luorophenyl ) urea
mp : 204-206°C
IR (KBr) : 3413, 3066, 1664, 1610, 1520, 1223 cra"l
NMR (DMSO-dg, 6) : 4.51 {2H, s), 4.55 (2H, s), 6.65
35 (IH, d, J=2.3Hz), 7.10-7.50 (9H, m) , 7.55-7.90
20
25
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(2H, m), 8.46 (IH, s), 12.89, 13.30 (total IH,
each br)
APCI-MASS (m/z) : 455 (M+H+)
(5) 1-Cycloheptyl-l- [4- [2- ( lH-tetrazol-5-
yl ) phenyl ] benzyl ] -3- (2 , 4 , 6-trimethylphenyl ) urea
IR (KBr) : 3408, 3310, 2924, 2856, 1620, 1605,
1506
NMR (DMSO-dg, 6) : 1.4-1.8 (12H, m) , 2.04 (6K, s),
2.20 (3H, s), 4.05-4.25 (IH, m) , 4.48 (2H, s),'
6.83 (2H, s), 7.04 (2H, d, J=7.9Hz), 7.23 (2h' d,
J=7.9Hz), 7.5-7.8 (5H, m)
FAB-MASS (m/z) : 509 (M+H+)
15 Exainnl^
To a solution of 1-cycloheptyl-l- [ 4- ( 4-
fluorophenoxy)benzyl]-3-[2,4-bis(raethylsulfonyl)-6-
methylpyridin-3-yl]urea (3.04 g) in methanol (100 ml) was
added sodium methanethiolate (315 mg) and the mixture was
stirred at 50°c for an hour under nitrogen. The mixture
was cooled to 5=C and the precipitates were collected bv
filtration, washed with methanol and diisopropyl ether and
dried in vacuo to give 1-cycloheptyl-l- [4- (4-
fluorophenoxy)benzyl]-3-(2-methylsulfonyl-4-methylthio-6-
methylpyridin-3-yl)urea (1.35 g) as a crystal.
IR (KBr) : 3377, 3072, 2926, 2858, 1657, 1572, 1498,
1473 cm-1
NMR (CDCI3, 5) : 1.5-2.1 (12H, m) , 2.44 (3H, s), 2.54
(3H, s), 3.23 {3H, s), 4.1-4.3 (IH, m) , 4.55 (2H,
s), 6.98 (IH, s), 6.9-7.1 (6H, m) , 7.35 (IH, d,
J=8.6Hz)
Example
20
35
To a stirred solution of 1-benzyl-l- [ 3- {pyra-ol-3-
yl ) benzyl ] -3- [2, 4-bis (methylthio) -6-methylpyridin-3-yl ] urea
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(1 g) in dichloromethane (8 ml) was added a solution cf m-
chloroperbenzoic acid (1.32 g) in dichloromethane (26 ml)
at O-S'C. After stirring for one hour at room temperature,
the mixture was washed with saturated sodium bicarbonate
aqueous solution, water and brine, dried over magnesium
sulfate, evaporated in vacuo. The residue was
chromatographed on silica gel to give 1-benzyl-l- [ 3-
(pyrazol-3-yl)benzyl] -3- [2, 4-bis (methylsulf onyl ) -6-
methylpyridin-3-yl] urea (183.0 mg) and l-benzyl-1- [ 3-
(pyrazol-3-yl) benzyl] -3- [2, 4-bis (methyl sul finyl ) -6-
methylpyridin-3-yl ] urea (235.6 mg) .
1 -Benzyl- 1- [3- (pyrazol-3-yl) benzyl ] -3- [2, 4-
bis (methylsulf onyl ) -6-methylpyridin-3-yl ] urea
15 (KBr) : 3344, 2924, 1655, 1493, 1313, 1238,
113 6 cm~l
NMR (DMSO-dg, 5) : 2.70 {3H, s), 3.32 (6H, s), 4.52
(4H, br s), 6.75 (IH, br s), 7.20-7.85 (lOH, m) ,
8.13 (IH, s), 8.66 (IH, s), 12.87, 13.22 (total
IH, each br)
APCI-MASS (m/z) : 554 (M+H"^)
1-Benzyl-l- [3- (pyrazol - 3- yl ) benzyl ] -3- [2, 4-
bis (methylsulf inyl ) - 6-methylpyridin- 3-yl ] urea
25 IR (KBr) : 3217, 2922, 1651, 1495, 1236, 1038,
9 60 cm"l
NMR (DMSO-dg, 6) : 2.60-2.80 (9H, m) , 4.42-4.75 {4K,
m) , 6.71 (IH, br s), 7.15-7.85 (IIK, m) , 8.84,
8.96 (total IH, each s), 12.93, 13.35 (total IK,
30 each br)
APCI-MASS (m/z) : 522 (M+H"*" )
Example 27
To a solution of N-cycloheptyl-4 - ( 4-
35 f luorophenoxy) benzylamine (1.57 g) in toluene (40 ml) were
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added 2, 4-dichloro-6-methyl-3-phenoxycarbonylaminopyridine
(1.49 g) and triethylamine (1.52 g) , and the mixture was
stxrred at lOO'C for 3 . 5 hours. The mixture was ooured
into a mixture of ethyl acetate and ice water, and the
5 separated organic layer was washed with brine, dried over
magnesium sulfate and evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give 1-
cycloheptyl-1- [4- (4-fluorophenoxy)benzylJ-3- (2, 4-dichloro-
6-methylpyridin-3-yl)urea (916 mg) .
'° ^^^^^ ■ 3365, 3275, 3062, 2927, 2858, 1653, 1581,
1543, 1497 cm"l
NMR (CDCI3, 5) : 1.5-2.1 (12H, m) , 2.47 (3H, s) , 4.2-
4.4 (IH, m), 4.53 (2H, s), 5.89 (IH, s), 6.9-7.1
(6H, m), 7.14 (IH, s), 7.36 (2H, d, J=8.7H2)
15 APCI-MASS (m/2) : 520, 518, 517 (M+H+)
ExamnlP p»
The following compounds were obtained according to a
similar manner to that of Example 7, 8, 9, 10, 13, 14 15
20 16, 17 or 27.
(1) l-Cycloheptyl-l-[4-(4-fluorophenoxy)ben2yl]-3-[ (2-
methoxy-4-methylthio-6-methyl)pyridin-3-yl]urea
IR (KBr) : 3371, 3064, 2926, 2856, 1666, 1585,
1498 cm-1
NMR (CDCI3, 5) : 1.5-2.1 (12H, m) , 2.38 (6H, s), 3.79
(3H, s), 4.2-4.4 (IH, m) , 4.52 (2H, s), 5.66 (IH,
br s), 6.53 (IH, s), 6.9-7.1 (6H, m) , 7.35 (IH,
d, J=8.7Hz)
30 APCI-MASS (m/z) : 524 (M+H+)
(2) l-Benzyl-l-[4-(4-fluorophenoxy)benzyl]-3-(2-chloro-4-
methylthio-6-methylpyridin-3-yl) urea
IR (KBr) : 3294, 3061, 3030, 2924, 1651, 1576,
3^ 1497 cm-1
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■15
NMR (CDCI3, 5) : 2.42 (3H, s), 2.47 (3H, s), 4 . 61 '
(2H, s), 4.63 {2H, s), 5.96 (IH, s ) 6.82 {IH,
s), 6.9-7.1 (6H, m), 7.25-7.45 (7H, m)
(3
1-Benzyl-l- [3- (l-methylpyrazol-4-yl)benzyl] -3- [2, 4-
bis (methylthio) - 6-methylpyridin-3-yl ] urea
mp : 137-138°C
IR (KBr) : 3255, 2922, 1651, 1562, 1493, 1228,
982 cm~l
10 NMR (DMSO-dg, 6) : 2.42 (6H, s), 2.47 (3H, s), 3.87
(3H, s), 4.66 (2H, br s), 4.48 (2H, br s), 6.90
(IH, s), 7.13 (IH, d, J=7.4Hz), 7.20-7.55 {8H,
m) , 7.81 (IH, s), 8.06 (IH, s), 8.29 (IH, s)
APCI-MASS (m/z) : 504 (M+H+)
(4)
1-Cycloheptyl-l- [3- ( l-methylpyrazol-4-yl) benzyl ] -3-
[2, 4-bis (methylthio) -6-methylpyridin-3-yl ] urea
mp : 197-198°C
IR (KBr) : 3290, 2924, 2854, 1653, 1485, 1227 cm"!
20 NMR (DMSO-dg, 6) : 1.25-1.90 (12H, m) , 2.40 (6H, s),
2.45 (3H, s), 3.87 (3H, s), 3.98-4.17 (IH, m) ,
4.48 (2H, br s), 6.87 (IH, s), 7.15 (IH, d,
J=7.5Hz), 7.27 (IH, dd, J=7.5, 7.5Hz), 7.38 (IH,
d, J=7.5Hz), 7.52 (IH, s), 7.80 (IH, s), 7.90
2^ (IH, br s) , 8 . 04 (IH, s)
APCI-MASS (m/z) : 510 (M+H+)
(5) 1- (2-Methoxybenzyl) -1- [3- (pyrazol-3-yl ) benzyl ] -3- [2,4-
bis (methylthio) -6-methylpyridin-3-yl ] urea
^° (KBr) : 3220, 2922, 1649, 1562, 1491, 1240 cm"-
NMR (DMSO-dg, 6) : 2.41 (6H, s), 2.46 (3H, s), 3.73
(3H, s), 4.44 (2H, br s), 4.53 (2H, br s), 6.67
(IH, br s), 6.88 (IH, s), 6.90-7.05 (2H, m) ,
7.15-7.90 (7H, m) , 8.19 (IH, br s), 12.89, 13.30
(total IH, each br)
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10
15
20
25
30
35
- 205 -
APCI-MASS (m/z) : 520
b.s(methylthio)-6-.ethylpyrxdin-3-yljurea
•• 165-166°C
<KBr, : 3.00, 3248, 3099, 2926, 1.^4, :«3, 1225
1049 citl-l '
NMR (DMSO-dc, 61 ■ 9 ^1
3H 4. 6 ,2H, 3,, 4.50 ,2„, 3., S.SB-
'total IH, ei"'
APCI-MASS im/z) :
methylthio-6-„ethylpyridir.-3-yl ) urea
XR <KBr, . 3230, 2922, 1647, 1576, 1497, 1333, 1279
1232 cm-1 '
NMR (DMSO-d^-, 5) - o ac, ,
I' ■ 2.45 (6h, s), 4.51 br s),
, r ° ^-17-7.85 (lOH
--31 (to.al IH, ea^.
APCI-MASS (xn/z) : 478, 480 (M.H^)
(8) 1- (4-Methoxybenzyl)-i-r4_ M-r-in^^ u
f 2, 4-bxs (n^ethylthio) -6-xnethylpyridxn-3-yl 1 u^ea'
mp : 130-l3l°c ' ~
IK (KBr, : 3404, 2995, 2924, 2833, 1674, 1610, 156.
1493, 1250, 1211 cm-1
NMR (CDCl^, 6) • P
3' • 2.39 (3h, s) , 2.49 (3H, s) , 2 5^
f^H, s), 3.81 (3H, s), 4.56 (2H, s), 4.58
5-72 (IH, s), 6.64 (IH, 3), 6.85-7 1. ( '
m). 7.20-7.38 (4H, m)
APCI-MASS (m/z) : 564 (M+H+)
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- 2Cc -
(9) 1-Benzyi-l- [4- ( 4-f luorophenoxy ) benzyl] -3- [2, 4-
dichloro- 6-methylpyr idin-3-yl ) urea
IR (KBr) : 3302, 3066, 3032, 2924, 1639, 1581, 1543,
14 97 cm"-
NMR (CDCI3, 5) : 2.48 (3H, s), 4.53 (2H, s), 4.64
{2H, s), 6.05 (IH, br s), 5.9-7.4 ;i4H, rr.) ,
APCI-MASS (m/2) : 514, 512, 510 (M+H~;
(10) 1- ( 3-Phenylpropyl ) -1- [4- ( 4-f luorophenoxy ) benzyl ] -3-
10 [2, 4-bis (methylthio ) -6-methylpyridin-3-yl ] urea
IR (KBr) : 3290, 2922, 1649, 1562, 1497, 1211,
10 93 cm"^
NMR (CDCI3, 5) : 1.92-2.13 (2H, m) , 2.38 (3H, s),
2.48 (3H, s), 2.49 (3H, s), 2.68 (2K, t,
15 J=7.7Hz), 3.39 (2H, t, J=7.6Kz), 4.57 (2H, s),
5.57 (IH, s), 6.63 (IH, s), 6.87-7.10 (6H, m) ,
7.10-7.37 (7H, m)
APCI-MASS (m/z) : 562 (M-rH"^)
20 (11) 1- {2-Phenylethyl) -1- [3- (pyrazol-3-yl)benzyl]-3- [2, 4-
bis (methylthio) - &-methylpyridin- 3-yl ] urea
IR (KBr) : 3209 (br), 2922, 1647, 1562, 1491, 1338,
1238 cm"l
NMR (DMSO-dg, 5) : 2.42 (6H, s), 2.47 (3K, si, 2.80-
25 2.98 (2H, m) , 3.35-3.54 (2H, m) , 4.44 (2K, s),
6.65 (IH, br s), 6.90 (IH, s), 7.1C-7.45 (7H, m) ,
7.45-7.83 (3H, m) , 8.13 (IH, s), 12.87, 13.30
(total IH, each br)
APCI-MASS (m/z) : 504 (M+H"^)
30
(12) 1- [ (S) -1-Phenylethyl] -1- [4- ( 4-f luorophenoxy) benzyl] -3-
[2, 4-bis (methylthio) -6-methylpyridin-3-yl ] urea
IR (KBr) : 3373, 3310, 29~S, 2924, 1550, 1562, 1497,
1246, 1211 cm"-
35 NMR (CDCI3, 6) : 1.63 (3H, d, J=7.1Hz}, 2.37 ;3H, s).
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207 -
2.4 6 ;3H, s) , 2.4 7 (3H,
, 7 f - TJ
J=17.2Hz), 4.50 (IH, d, J=17.2Hz), 5.53 {
5.7 5-5.92 (IH, n) , 5.5 0 (IH, s .- ^ Qa_-7
-n , s
a ; , o . Ba- / . 1 0 ' ch
m) , 7. 22-7. 50 (7:-;, .-n;
APCI-MASS im/z] : 54 6 (.M-;-:-;
(13) 1- [ (R) -1-PhenylechylJ -1- [4- (4-flucrcphenoxy) ben
[2, 4-bis (meEhylthio) -6-me-hylpyridi--3-vl j un
ZVj. I
IR (KBrJ : 3369, 3309, 297S, 2924, 1659, 1562, 149-
1246, 1211 c.-r."!
NMR (CDCI3, 5) : 1.63 ;3K, ci, J=7 . IH:
2.3"? ;3H
2.46 (3K, s), 2.47 (3H, s), 4.27 (IH, d,
J=17.2Hz), 4.50 (IH, d, J=17.2H2), 5.5
T f -, U ~ \
5./5-5.92 (IH, n) , 6.50 (IH, s], 5.98-7.10 (6H,
m) , 7.22-7.50 (7H, n)
MASS (m/z) : 548 (M+H^)
-62.2° (C =1.02, CHCl,)
(14) 1-Cycloheptyi-l- [4- ( 4-f luorophenoxy) benzvl ] -3- ;4-
chloro-2-metnylthic-6-methylpyridir.-3-yi j urea
IR (KBr) : 3371, 3275, 3062, 2926, 2856, 1653, 1560,
1498 cm~l
NMR (CDCI3, 5) : 1.4-2.1 (12K, m) , 2.44 (3H, s), 2.4
(3H, s), 4.25-4.45 (IK, n) , 5.61 (2H, s;, 5.89
(IH, s) , 6.9-7.1 (6H, in), 7.37 (2H, d, J=S.6Hz)
APCI-MASS (m/z) : 530, 528 (M+H"^ )
(15) l-3enzyl-l-[4- ( 4-f luorophenoxy ) benzyl ] -3- ( 4 -chlcro-2 -
nierhylt.hio-6-inethylpyridin-3-yl ) urea
IR (KBr) : 3275, 3062, 3030, 2924, 1645, 1550,
14 97 crrrl
MMR (CDCI3, 6) : 2.46 (3H, s), 2.49 (3H, s), 4.61
(2H, s), 4.63 (2H, s), 5.80 (IH, br s), 6.9-7.1
(7K, m) , 7.2 5-7.4 (7H, m)
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APCI-MASS (m/z) : 524, 522 (M+H+)
(16) 1-Cycloheptyl-l- [4- ( 4-bromophenoxy) benzyl] -3- [2-
chloro-4-methylthio-6-methylpyridin-3-yl ] urea
mp : 105-107°C
5 IR (KBr) : 3379, 2926, 2854, 1668, 1579, 1483,
1238 cm~^
NMR (CDCI3, 5) : 1.38-2.08 (12H, m) , 2.41 (3H, s),
2.48 (3H, s), 4.20-4.40 (IH, rp.) , 4.54 (2H, s),
5.76 (IH, s), 6.82 (IH, s), 6.82-6.93 (2H, m) ,
10 6.95-7.08 (2H, m) , 7.32-7.50 {4H, m)
APCI-MASS (m/z) : 588, 590, 592 (M+K"^)
( 17 ) 1 -Benzyl- 1- [4 - ( 4-broinophenoxy ) benzyl ] -3- [2-chloro-4-
methylthio-6-methylpyridin-3-yl ] urea
15 IR (KBr) : 3280, 3030, 2920, 1651, 1578, 1504, 1435,
1236, 804 cm"^
NMR (CDCI3, 5) : 2.43 {3K, s), 2.49 (3H, s), 4.63
(2H, s), 4.64 (2H, s), 5.93 (IH, s), 6.84 (IH,
s) , 6.84-6-94 (2H, m) , 6.94-7.07 (2H, m) , 7.22-
20 7.50 (9K, m)
APCI-MASS (m/z) : 582, 584, 566 (M+H"^)
(IB) 1-Cycloheptyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- [2-chloro-
4-methylthio-6-methylpyridin-3-yl] urea
25 mp : 165-166°C
IR (KBr) : 3205, 2926, 2856, 1624, 1572, 1491,
8 0 4 cm" ^
NMR (DMSO-dg, 5) : 1.30-1.90 (12H, m) , 2.43 (6H, s),
4.00-4.18 (IH, m) , 4.53 (2H, br s), 6.55-6.67
30 (IH, m) , 7.12 (IK, s), 7.20-7.83 (5H, m) , 8.11
(IH, br s), 12.85, 13.28 (total IH, each br s)
APCI-MASS (m/z) : 484, 486 (M+H"^ )
Example 2 9
The following compound can be obtained by treating 1-
3 5 benzyl- 1- [3- (pyrazol-3-yl ) benzyl ] -3- [2, 4 -bis (methylthio) -6-
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- 209 -
methylpyridin-3-yl ] urea with hydrochloric acid or
hydrochloride in a conventional manner.
l-3enzyl-l- [3- (pyrazol-3-yl ) benzyl ] -3- [2, 4-
bis (methylthio) -6-methylpyridin-3-yl ] urea-hydrochloride
5
Example 30
The following compound can be obtained by treating 1-
benzyl-1- [3- (pyrazol-3-yl ) benzyl ] -3- [2, 4 -bis (methylthio) -6
methylpyridin-3-yl ] urea with sulfuric acid in a
0 conventional manner.
1 -Benzyl- 1- [3- (pyrazol-3-yl ) benzyl]-3-[2,4-
bis (methylthio) -6-methylpyridin-3-yl ] urea-sulf ate
Example 31
5 The following compound was obtained according to a
similar manner to that of Example 19.
1-Benzyl-l- [4- ( 4 - fluorophenoxy) benzyl ] -3- [2, 4-
bis (methylsulfonyl) - 6-methylpyridin-3-yl ] urea
IR (KBr) : 3348, 3066, 3030, 2927, 1734, 1668, 1610,
0 1583, 1497 cm~^
NMR (CDC13, 5) : 2.67 (3K, s), 3.20 (3K, s), 3.32
(3H, s), 4.6-4.7 (4H, m) , 6.9-7.1 ( 6H, m) , 7.3-
7.5 (2H, m) , 7.62 (IH, br s), 7.88 (IH, s)
APCI-MASS (m/z) : 598 (M+H"*")
Example 32
The following compound was obtained according to a
similar manner to that of Example 29.
l-Cycloheptyl- 1- [4- ( 4- fluorophenoxy) benzyl] -3- (2, 4 , 6-
trimethylpyridin-3-yl ) urea hydrochloride
mp: 176-178°C
NMR (DMSO-dg, 6) : 1.35-1.9 (12K, m) , 2.32 (3H, s),
2.52(3H, s), 2.65 (3H, s), 4.1-4.3 (IH, m; , 4.53
(2H, s), 6.95-7.4 (8H, m) , 7.61 (IK, s), 8.30(1H,
br s)
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CLAIMS
1. A comDound of the formula
0
R^- (CH2 ) ^-N-C-NH-r3
7
wnerem
R-^ is a group of the formula
(in which
is aryl which may have suitable
substituent ( s ) , or heterocyclic group which
may have suitable subst i tuenr ( s ) , and
II
Y is bond, lower alkylene, -S-, -0-, -C-,
=CH-, -CONH-, -N-CO-, (in which r"^ is lower
r" alkyl),
-NHSO2-, -SO7NH-, -SO2NHCO- or -CONHSO9-) ;
or
thiazolyl, imidazolyl, pyrazolyl, pyridyl,
thienyl, furyl, isoxazolyl or chromanyl , each of
which may have suitable subs ti tuent ( s ) ;
R is lower alkyl, lower alkoxy (lower) alkyl,
cycloalkyl, ar ( lower ) alkyl which may have
suitable subs t ituent ( s ) , heterocyclic group or
heterocyclic (lower) alkyl,
R-^ is aryl which may have suitable substituent (s ) or
heterocyclic group which may have suitable
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- 211 -
substituent (s) , and
n is 0 or 1,
and a pharmaceutically acceptable salt thereof,
2. A compound of claim 1, wherein
is a group of the formula :
r4
(in which
is phenyl which may have 1 to 3 substituent { s )
selected from the group consisting of
halogen, lower alkyl, di (lower ) alkylamino,
protected amino, cyano, heterocyclic group
which may have mono (or di or tri)-
ar (lower) alkyl, hydroxy, protected hydroxy
and mono (or di or tri ) halo ( lower ) alkyl ;
or thienyl, pyrazolyl, imidazolyi,
triazolyl, pyridyl, pyrrolyl, tetrazolyl,
oxazolyl, thiazolyl, oxadiazolyl,
piperazinyl, thiazolidinyl or
methylenedioxyphenyl, each of which may have
1 to 3 substituent (s) selected from the
group consisting of lower alkyl, mono (or di
or tri) ar (lower) alkyl and oxo;
O
Y is bond, lower alkylene, -s-, -o-, -c-, =CH-,
-CONH-, -N-CO- (in which is lower ' al kyl )' ,
r7
-NHSO2-, -SO2NH-, -SO2NHCO- or -CONHSO.-
or
9-) ;
thiazolyl, imidazolyi, pyrazolyl, pyridyl.
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thienyl, furyl, isoxazolyl or chromanyl , each of
which may have 1 to 5 subs t i tuent ( s ) selected
from, the group consisting of lower alkyl,
hydroxy, protected hydroxy, phenyl, halophenyl,
5 phenylthio and pyrrolyl;
is lower alkyl; lower alkoxy ( lower ) alkyl , •
cyclo (€3-0-7 ) alkyl ; phenyl ( lower ) alkyl which may
have 1 to 3 substi tuent ( s ) selected from the
group consisting of halogen, lower alkoxy and
10 di (lower alkyl) amino; tetrahyciropyranyl ; or
furyl ( lower) alkyl ;
R-^ is. phenyl which may have 1 to 3 substi tuent ( s )
selected from the group consisting of lower alkyl
and halogen; pyridyl or pyrimidinyl, each of
15 which may have 1 to 3 substituent ( s ) selected
from the group consisting of lower alkyl, lower
alkylthio, halogen, lower alkoxy, lower
alkylsulf inyl and lower alkylsulf onyl .
20 3. A compound of claim 2, wherein
R-'- is a group of the formula :
(in which
R*^ is phenyl which may have 1 to 3 subs t ituent ( s )
selected from the group consisting of
halogen, lower alkyl, di { lower) alkylamino,
acylamino, cyano, tetrazolyl which may have
mono (or di or tri ) phenyl ( lower ) alkyl ,
hydroxy, lower alkoxy ( lower ) alkoxy and
mono (or di or tri ) halo ( lower ) alkyl ; or
thienyl, pyrazolyl, imidazolyl, triazolyl,
PCT/JP95/01982
- 213 -
pyridyl, pyrrolyl, tetrazo-lyl, oxazolyl,
thiazolyl, oxadiazolyl, piperazinyl,
thiazolidinyl or methyl enedioxyphenyl , each
of which may have one or two substituent (s )
selected from the group consisting of lower
alkyl, phenyl (lower) alkyl, triphenyl (lower) -
alkyl and 0x0/
Y is bond, lower alkylene, -S-, -o-, -c- =ch-
-CONH-, -N-CO- (in which 13 iower ' al kyi )' ,
-NHSO2-, -SO2NH-, -SO2NHCO- or -CONHSOp-);
or
thiazolyl, imidazolyl, pyrazolyl, pyridyl,
thienyl, furyl, isoxazolyl or chromanyl, each of
Which may have 1 to 5 substituent ( s ) selected
from the group consisting of lower alkyl,
hydroxy, acyloxy, phenyl, halophenyl, phlnylthio
and pyrrolyl;
is lower alkyl; lower alkoxy (lower ) alkyl ;
cyclo(C3-C7) alkyl; phenyl (lower) alkyl which may
have one or two substituent (s ) selected from the
group consisting of halogen, lower alkoxy and
di (lower alkyl) amino; tetrahydropyranyl ; or
furyl (lower) alkyl; and
is phenyl which may have two or three
substituents selected from the group consisting
of lower alkyl and halogen; pyridyl or
pyrimidinyl, each of which may have two or three
substituents selected from the group consisting
of lower alkyl, lower alkylthio, halogen, lower
alkoxy, lower alkylsulf inyl and lower
alkylsulfonyl .
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4. A compound of claim 3, wherein
R-'- is a group of the formula :
(in which
is phenyl; halopheny; lower alkylphenyl ;
di (lower) alkylaminophenyl ; lower
alkylsulf onylaminophenyl ; cyanophenyl ;
tetrazolylphenyl ; (triphenyl (lower) -
alkyl tetrazolyl ) phenyl; rrihalo (lower) -
alkylphenyl; phenyl having two lower alkyl
and hydroxy; phenyl having two lower alkyl
and lower alkoxy { lower ) alkoxy; thienyl;
pyrazolyl which may have lower alkyl or
triphenyl ( lower ) alkyl ; imidazolyl; triazolyl
which may have one or two substituent { s )
selected from the group consisting of lower
alkyl and phenyl ( lower ) alkyl ; pyridyl;
pyrrolyi; tetrazolyl which may have lower
alkyl or triphenyl { lower ) alkyl ; oxazolyl;
lower alkylthiazolyl ; lower alkyioxa-
diazolyl; lower alkylpiperazinyl ;
dioxothiazolidinyl ; or
methylenedioxyphenyl ] ; and
O
II
Y is bond, lower alkylene, -S-, -0-, -C-, =CH-,
-CONH-, -N-CO- (in which r"^ is lower alkyl) ,
-NHSO2-, -SO2NH-, -SO2NKCO- or -CONHSO2-) ;
halophenylthiazolyl ; phenylimidazolyl ;
phenylpyrazolyl ; phenylpyridyl ;
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phenyl thiopyridyl; pyrrolylpyridyl ;
phenylthienyl; phenylfuryl; phenylisoxazolyi; oi
chromanyl having 4 lower alkyl and hvdroxy;
R is lower alkyl, lower alkoxy (lower) alkvl,
cycle (C3-C7) alkyl, phenyl (lower) alkyl,
halophenyl (lower) alkyl, lower
alkoxyphenyl ( lower) alkyl , di.(lower
alkyl) aminophenyl (lower) alkyl, tetrahydropyranyl
or furyl (lower ) alkyl, and
R-^ is pyridyl having two lower alkyl thio and lower
alkyl; pyridyl having halogen, lower alkyl and
lower alkyl thio; tri (lower alkyl ) pyridyl ;
pyridyl having two lower alkoxy and lower alkyl;
pyridyl having lower alkoxy, lower alkylthio and
lower alkyl; pyridyl having two lower alkyl-
sulfinyl and lower alkyl; pyridyl having two
lower alkylsulf onyl and lower alkyl; pyridyl
having lower alkylthio, lower alkoxy and lower
alkyl; pyridyl having lower al kyl sul f inyl , lower
alkylsulfonyl and lower alkyl; pyridyl having
lower alkylthio, lower alkylsulfonyl and lower
alkyl; pyridyl having two halogen and lower
alkyl; di ( lower ) alkoxypyrimidinyl ; or pyrimidinyi
having two lower alkylthio and lower alkyl.
A compound of claim 4, wherein
R-'- is a group of the formula :
(in which R- is phenyl or halophenyl, and
Y is -0-) ,
PCT/JP95/01982
- 216 -
r2 is cyclo (C3-C7) alkyl or phenyl ( lower ) alkyl ,
R'^ is phenyl having two lower alkylthio and lower
alkyl; tri (lower alkyl ) pyridyl ; pyridyl having
two halogen and lower alkyl; pyridyl having
halogen, lower alkyl and lower alkylthio; pyridyl
having lower alkyluhio, lower alkoxy and lower
alkyl; pyridyl having lower alkylthio, lower
alkylsulfonyl and lower alkyl; pyridyl having two
lower alkylsulfonyl and lower alkyl; or
pyrimidinyl having two lower alkylthio and lower
alkyl; and
n is 1 .
A compound of claim 5, wherein
R-'- is a group of the formula :
(in which R"* is halophenyl, and
Y is -0-) ,
• is cyclo (C3-C7 ) alkyl, and
' is tri (lower alkyl ) pyridyl ; or
pyridyl having two lower alkylsulfonyl and lower
alkyl .
compound of claim 4, wherein
is a group of the formula :
(in which R^ is pyrazolyl and
Y is bond) ,
wo 96/10559
PCT/JP95/01982
10
25
30
- 217 -
is phenyl (lower) alkyl, lower
R
alkoxyphenyl (lower) alkyl, halophenyl ( lower ) alkyl
di (lower) alkylaminophenyl (lower) alkyl or
cyclo (C3-C7) alkyi,
is pyridyl having two lower alkylthxo and lower
alkyl; pyridyl having halogen, lower alkvl and
lower alkylthio; or pyrixnidinyl having two low
alkylthio and lower alkyi; and
n is 1 .
er
A compound of claim 7, wherein
R- is a group of the formula :
15 r4-Y-^^^
(in which r4 is pyrazolyl, and
Y is bond) ,
ower) alkyi, and
R-^ is pyridyl having two lower alkylthio and lower
2 0 R~ is phenyl (1
,3
alkyi .
9. A process for preparing a compound of the formul.
0
R^-(CH2)j,-N-C-NK-r3
wherein
R^ is a group of the formula :
35
wo 96/10559
PCT/JP95/01982
- 218 -
(in v/hich
R IS aryi which -.ay nave suicable
subsrituem: ( s ) ,■ or heterocyclic group which
may have suitable substiruenr ( s ) , and
0
!i
Y is bond, lower alkylene, -S-, -0-, -C-, =CK-,
-CONK-, -N-CO-, (in which r"^ is lower
r7 alkyl) ,
-NHSO2-, -SO2NH-, -SO2NHCO- or -CONHSO2-/;
or
thiazolyl, imidazolyl, pyrazolyl, pyridyl,
thienyl, furyl, isoxazolyl or chronanyl, each of
which may have suitable substi tuent ( s ) ;
R^ is lower alkyl, lower alkoxy (lower) alkyl,
cycloalkyl, ar (lower) alkyl which may have
suitable substituent ( s ) , heterocyclic group or
heterocyclic (lower) alkyl,
R-" is aryl v;hich may have suitable subst i ruent ( s ) or
heterocyclic group which may have suitable
substituent ( s ) , and
n is 0 or i,
or a salr thereof,
which comprises
(1) reacting a compound of the formula :
(CH2 ) n~^^-
wo 96/10559
PCT/JP95/01982
a
- 219 •-
wherein R^, r2 and n are each as defined ^bove,
or a salt thereof with a compound of the formul
o=c=n-r2
wherein R^ is as defined above,
or a salt thereof to give a compound of the formula
O
1 (I
R^- (CH2 )n-N-C-NH-R3
r2
wherein r\ r2, r3 ^ ^^^^^ defined above,
or a salt thereof,
or
12) subjecting a compound of the formula :
R^- (CHo) ^-NH
R^
wherein r1, r2 and n are each as defined above,
or a salt thereof and a compound of the formula :
H2N-R^
wherein R^ is as defined above, or a salt thereof to
formation of ureido group to give a compound of the
formula :
wo 96/10559
PCT/JP95/01982
- 220 r-
0
R^- (CH2 ) r^-N-C-NH-R^
R-
wherein r1, r2, r3 n are each as defined above,
or a salt thereof,
or
(3) subjecting a compound of the formula :
0
R^- {CH2 ) n-N-C-NH-R|
ii2
wherein R^, r2 and n are each as defined above, and
pyridyl ha\
lower alkyl,
reof to ox
compound of the formula
pyridyl having two lower alkylthio and
lower alkyl,
or a salt thereof to oxidation reaction to give a
O
R^- (CH2 ) n-N-C-NH-R|
r2
wherein R^, r2 and n are each as defined above, and
Rb is pyridyl having two lower alkylsulf onyl
wo 96/10559
PCT/JP95/01982
- 221 -
11
12,
13
and lower alJcyl; pyridyl having two
lower alJcylsulfir.yl and lower alkyl • o
pyridyl having lower alkylsulf ony ^
alkylsulfinyl and lower alJcyl •
or a salt thereof. ^-^Y-t,
■ cir'rr""""' -.posicion .o.^r,s,n, a compound of
,1 " " in association with
a P ™aceuticaiav .ccepta.ie, su^stantiaXi, no„-to.ic
carrier or excipient.
A compound Of Claim 1 for use as a medicament.
A method of therapeutic treatment and/or prevention of
hyperchoiesteroxemia, h.vperiipidemia, athLscT r" is
or diseases caused thereby which comprises
administering an effective amount of ' a compound of
Claim 1 to human beings or animals.
use Of a compound of claim 1 for the manufacture of a
medicament for treating and/or preventing
hypercholesterolemia, hyperlipidemia, atherosclerosis
Of diseases caused thereby in human beings or animals.
INTERNATIONAL SEARCH REPORT
Intcnur A -^aon No
PCT/JP 9b/01982
A CLASSIFICATION OF SUBJECT MATTER '
IPC 6 C07C275/28 C07D213/75 C07D257/04 C07D231/12
A61K31/17 A61K31/44 A61K31/41 C07D213/40
C07D277/28 C07D233/54 C07C311/21 C07D333/20
According to Intem«lion«l Patent Qasaficalion (IPC) or to both national class ncation and IPC
C07D401/12
C07D307/38
B. FIELDS SEARCHED
Minimum documentation searched (claaification system followed by clasaficabon symbols)
IPC 6 C07C C07D
DocumenUDon searched other than minimum documentanon to the extent that such documents are included in the fields searched
Electronic data base consulted dunng the intemaOonal search (name of daU base and, where practical, search ternis used)
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category *
Otaton of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
US, A, 4 623 662 (DE VRIES VERN G) 18
November 1986
cited in the application
see column 9, line 9 - line 16; examples
e.g. table 1, column 10, line 30 - line
35;
see column 11 and 12, line 50 - line 60;
claims 1-4
EP.A.O 399 422 (TAKEDA CHEMICAL INDUSTRIES
LTD) 28 November 1990
see page 3, line 7 - line 13; claims
1,13,16; example 64
FR,A,2 661 676 (LIPHA) 8 November 1991
see claim 1; compound 8, 31, 76, 79
see page 18, line 30 - line 37
-/--
1-3,12,
13
1-3.
10-13
1-3,12.
13
I X| F'"**>«'' documents are listed in the continuation of bojc C.
I )( [ Patent family members are listed m annex.
' Speaal categories of ated documents :
■A" document defuung the general state of the art which is not
considered to be of particular relevance
"E" earlier document but published on or after the international
filing date
'L' document which may throw doubts on prionty claim(s) or
which IS ated to establish the publicaDon date of another
citation or other speaal reason (as specified)
O" document refemng to an oral disclosure, use, exhibition or
other means
P' document published pnor to the international filing date but
later than the pnonty date claimed
'T' later document published after the intemaOonal filing date
or pnonty date and not in conflict with (he applicaoon but
ated to understand the pnnciple or theory undcilying the
mvenboa
'X' document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone
'Y' document of particular relevance; (he claimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person ikiUed
in the art.
'St' document member of the same patent family
Date of the actual completion of the international search
17 January 1996
Date of mailing of the international search report
«9. 01 96
Name and mailing address of the ISA
European Patent Office, P.B. 5il 8 Patentlaan 2
NL - 2280 HV Rijswijk
Td. ( + 31-70) 340-2040, Tx. 31 651 epo nl.
Fax (+ 31-70) 340-3016
Authorized officer
Seufert, G
Form PCT/ISA/3I0 {naxit iImm) (July 1993)
page 1 of 2
INTERNATIONAL SEARCH REPORT
• A' -«iaa No
PCT/JP 9a/01982
ion) DOCUMENTS CONSIDERED TO BE RELEVANT
CaMfory '
OtabOB or document, with mdicanoo. where appropnate, of the relevant paaatct
Relevant to claim No.
WO, A, 93 24458 (PFIZER ; HAMANAKA ERNEST S
(US)) 9 December 1993
cited In the application
see claims 1,9,10; examples 19,24
PATENT ABSTRACTS OF JAPAN
vol. 018 no. 575 (C-1268) ,4 November 1994
& JP,A,06 211814 (ONO PHARMACEUT CO LTD)
2 August 1994,
see abstract
CHEMICAL ABSTRACTS, vol. 121, no. 25,
19 December 1994
Columbus, Ohio, US;
abstract no. 292008,
R. E. OLSON ET AL.
see RN 159219-49-5
& BIORG. MED. CHEM. LETT..
vol. 4, no. 18, 1994
pages 2229-2234,
EP,A,0 576 357 (SANOFI ELF) 29 December
1993
see claims 1,16; examples 180,190
DE,A,21 32 431 (RIEDEL DE HAEN AG) 11
January 1973
see page 17, first example
GB,A.l 598 900 (LILLY INDUSTRIES LTD) 23
September 1981
see claims 1,18; examples 59,62
US, A, 5 169 844 (COMMONS THOMAS J ET AL) 8
December 1992
see column 1, line 8 - line 25; claims
1,21.22
EP,A,0 370 740 (WELLCOME FOUND) 30 May
1990
see page 3, line 1 - line 24; claims
1,11-15; examples
1-4,10,
12
1-4
1-3,10
1-3
1-3,10
1,5,
10-13
1,10-13
Fonn PCT/ISA/310 (CDnUniwaaa Df
i« ttiaM) (July IMI)
oaqe 2 of 2
INTERNATIONAL SEARCH REPORT
i Box I Obsenraiions where cemin daiina
Ii. aat iU application No.
PCT/JP 95/ 01982
were found unsevchable (Continuation of item I of first sheet)
I Thi. in«r„«io„x. .e^ch report h« not been esubUshcd in respect of cert«n cl.in,s under ArUc.e . 7(2Xa) for the followang ,
I I Claims Nos.:
□
Claims Nos.:
ir^^^-n^^l^XKntS'^^^^^ P--'^ -'^u-ements to such
Claims searched Incompletely: 1-4,9-13
I I Claims Nos.:
because they are dependent claims «.d are not drafted in ««,rd«,ce with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
[ This International Searchmg Authority found multiple inventions in this international applicauon. as follows:
*■ O «L^Ib?e"d:f,r!^?*""°"'' """" "^'^ '""•^'y P**" »PP''""'' mccrnational search report covers all
^' I— ' o/^ytd"!Son!S f^""' """"^ "I'li"''"^ fee. this
Authority did not invite payment
international search report
report is
Remark on Protest
I I Th« addiUonal search fees were accompanied by the appUcant's protest
I I No protest accompanied the payment of additional search fees.
orm PCT/ISA/710 (conunuaUon of first sheet (1)) (July 1992)
International Application No. PCT/JP 95/01982
FURTHER INFORMATION CONTINUED FROM PCT/ISA/
The definition of the substituents in claim 1 is too general and/or encom-
passes too broad a range of theoretically conceivable compounds so that a
comprehensive search is not possible.
For economic reasons the search has been limited to the following cases
(with regard to the disclosed examples):
R1 = .^-^ ^ with R4 = aryl or heterocyclic group and Y as
^^O;^ Y — ft. defined in claim 1
= -Cyl --Cy2 with Cyl = thiazolyl, imidazolyl, pyrazolyl, pyridyl, thienyl,
furyl, isoxazolyl or chromanyl as defined in claim 1 , and Cy2 as carbo-
or heterocyclic residue
INTERNAllONAL SEARCH REPORT
Iniudnau^ oo paKnl family membcn
Internat' Ar -^on No
PCT/JP 93/01982
Patent document
cited in search report
US-A-4623662
EP-A-0399422
FR-A-2661676
WO-A-9324458
EP-A-0576357
DE-A-2132431
GB-A-1598900
US-A-5 169844
EP-A-0370740
Publication
date
18-11-86
28-11-90
08- 11-91
09- 12-93
29-12-93
11-01-73
23-09-81
08-12-92
30-05-90
Patent family
member(s)
US-A-
5003106
AU-B-
AU-B-
CN-A-
CA-A-
JP-A-
632809
5518890
1047859
2017444
3261755
NONE
AU-B-
BG-A-
CA-A-
EP-A-
HU-A-
JP-T-
NO-A-
PL-A-
4028393
99188
2134359
0642498
64303
7503737
944530
299082
FR-A-
AU-B-
CA-A-
CZ-A-
HU-A-
JP-A-
NO-A-
NZ-A-
SK-A-
ZA-A-
2692575
4143893
2098944
9301172
64526
6073014
932296
247961
65493
9304511
NONE
NONE
AU-B-
WO-A-
3425193
9313067
AU-B-
AU-B-
CA-A-
638950
4536389
2003395
Publication
date
26-03-91
14-01-93
29-11-90
19-12-90
25-11-90
21-11-91
30-12-93
28-07-95
09-12-93
15-03-95
28-12-93
20-04-95
25-11-94
05-04-94
24-12-93
06-01-94
24-12-93
16-03-94
28-01-94
15-03-94
27- 12-93
28- 08-95
02-02-94
22-02-94
28-07-93
08-07-93
15-07-93
24-05-90
21-05-90
Form PCT/ISA/3ia (piunt famUy uinu) (July l»n)
page 1 of 2
INTERNATIONAL SEARCH REPORT
Iniucmat.^ on patent family memben
Inteniar ' Ar -abon No
PCT/JP 9d/01982
Patent document
cited in tearch report
Public&tion
dmte
Patent family
member(s)
Publication
date
DE-D-
68913762
14-04-94
DE-T-
68913762
23-06-94
EP-A-
0450660
09-10-91
ES-T-
2052028
01-07-94
ES-T-
2062610
16-12-94
Tl _A_
IL-A-
JP-A-
2188568
24-07-90
LT-A-
418
25-09-94
PL-B-
162010
31-08-93
RU-C-
2036901
09-06-95
US-A-
5395853
07-03-95
US-A-
5290814
01-03-94
EP-A-0370740
Foim PCT/ISA/aiO (patant funUy uintx) (July 1993)
page 2 of 2
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